Orally disintegrating tablet comprising amorphous solid dispersion of nilotinib

ABSTRACT

Amorphous solid dispersions and pharmaceutical compositions of the protein kinase inhibitor nilotinib. The pharmaceutical compositions may be used in methods of treating a proliferative disorder such as cancer. In particular, the present disclosure provides a pharmaceutical composition in the form of an orally disintegrating tablet. In some embodiments, the pharmaceutical compositions can be administered without regard to food consumption. In other embodiments, the pharmaceutical compositions can be administered at a significantly lower dose as compared to a commercially available immediate-release nilotinib formulation, while providing a comparable therapeutic effect.

REFERENCE TO RELATED APPLICATION

The present application is a continuation application of InternationalApplication No. PCT/US2021/030154, filed Apr. 30, 2021, which claims thebenefit of U.S. Provisional App. No. 63/018,213 (filed Apr. 30, 2020),U.S. Provisional App. No. 63/067,064 (filed Aug. 18, 2020), and U.S.Provisional App. No. 63/122,751 (filed Dec. 8, 2020), the entiredisclosures of which are hereby incorporated by reference.

BACKGROUND

Protein kinase inhibitors (PKIs) have been studied for their potentialuse in treating various disorders of cellular proliferation, includingcancer. The potential for PKIs as a treatment is based on the role thatprotein kinases are known to play in regulating many cellular pathways,including those involved in signal transduction. Dysregulation ofprotein kinases has been implicated in the development and progressionof many cancers, which suggests that PKIs may be useful as a treatmentfor disorders or diseases such as cancer that are caused by uncontrolledoverexpression or upregulation of protein kinases.

One such PKI is nilotinib, which is currently marketed as animmediate-release formulation for oral administration under the brandname TASIGNA. TASIGNA is indicated for (a) treatment of adult andpediatric patients greater than or equal to 1 year of age with newlydiagnosed Philadelphia chromosome positive chronic myeloid leukemia (Ph+CML) in chronic phase; (b) treatment of adult patients with chronicphase and accelerated phase Ph+ CML resistant or intolerant to priortherapy that included imatinib; and (c) treatment of pediatric patientsgreater than or equal to 1 year of age with chronic phase Ph+ CML withresistance or intolerance to prior tyrosine-kinase inhibitor therapy.

Presently, oral dosage of TASIGNA is accompanied by a food effect. Infact, the prescribing information for TASIGNA contains a boxed warningthat includes the statement, “[a]void food 2 hours before and 1 hourafter taking the dose.” According to the prescribing information,“[s]ignificant prolongation of the QT interval may occur when TASIGNA isinappropriately taken with food and/or strong CYP3A4 inhibitors and/ormedicinal products with a known potential to prolong QT. Therefore,co-administration with food must be avoided. . . . ” This effect on theQT interval is likely due to the increase in exposure (expressed asarea-under-the-curve, or AUC) and/or maximum plasma concentration(C_(max)) that can occur when TASIGNA is taken with food. For example, asingle 400-mg dose of TASIGNA taken 30 minutes after a high-fat meal,increased AUC and C_(max) by 82% and 112%, respectively, as compared tolevels obtained under fasting conditions. Such an increase in serumlevels may also exacerbate or increase the prevalence of common sideeffects such as nausea, diarrhea, rash, headache, muscle and joint pain,tiredness, vomiting, and fever; as well as more serious side effectssuch as low blood cell counts, decreased blood flow to the heart orbrain, pancreas inflammation, liver problems, and bleeding problems.

The current prescribing information for TASIGNA instructs the patient todose TASIGNA twice daily on an empty stomach, and avoid food 2 hoursbefore and 1 hour after taking a dose. The requirement to take TASIGNAtwice-a-day without food (for a three-hour period for each dose) is aconsiderable burden to patients. Further, in light of the side effectsthat can occur with TASIGNA, poor adherence to the dosingrecommendations can be very detrimental to patients.

In addition, the solubility of nilotinib significantly decreases withincreasing pH, and therefore nilotinib absorption may be compromised ifTASIGNA is administered along with gastric acid-reducing agents. Use ofTASIGNA with common gastric acid-reducing agents is restricted inaccordance with prescribing information. For example, the prescribinginformation for TASIGNA states, “[a]void concomitant use of [proton pumpinhibitor] with Tasigna.” The prescribing information further suggeststo “[u]se short-acting antacids or H₂ blockers as an alternative toproton pump inhibitors” because “[c]oncomitant use with a [proton pumpinhibitor] decreased nilotinib concentrations compared to Tasigna alone. . . which may reduce Tasigna efficacy.” For safe use of TASIGNA withgastric acid-reducing agents, the following instruction is provided inthe prescribing information: “As an alternative to PPIs, use H₂ blockersapproximately 10 hours before or approximately 2 hours after the dose ofTasigna, or use antacids approximately 2 hours before or approximately 2hours after the dose of Tasigna.” These restrictions on how patients canaddress indigestion or excess gastric acidity while treated with TASIGNAare burdensome, especially in light of how often such symptoms can occurwithin the patient population. Moreover, poor adherence to theprescribing information's warnings about taking gastric acid-reducingagents while being treated with TASIGNA can be detrimental to thepatient.

Furthermore, it is known that certain patients sometimes have difficultyswallowing an intact solid oral dosage form (such as a hard gelatincapsule). This can be especially challenging for elderly or geriatricpatients and pediatric patients, for example. Patients suffering fromdysphagia for any reason also experience difficulty swallowing an intactsolid oral dosage form.

For such patients suffering from a proliferative disorder, analternative method of dosing nilotinib is highly beneficial. U.S. Pat.No. 9,061,029 describes one alternative approach for such patients,whereby the swallowing problem described above is alleviated by oraladministration of nilotinib dispersed in a fruit preparation. It wasfound that a single oral administration of 400 mg nilotinib (contents oftwo 200 mg immediate-release nilotinib capsules), each dispersed in oneteaspoon of applesauce, is bioequivalent to a single oral administrationof 400 mg nilotinib given as intact capsules. However, the same amountdispersed in plain non-fat yogurt was not found to be bioequivalent.Therefore, while beneficial as an alternative dosage method, thisapproach still suffers generally from the same food-effect problem asdescribed above, and likewise, use with gastric acid-reducing agentsremains restricted.

Thus, there remains a need in the art for a means for patients toreceive the full benefits of nilotinib while minimizing the risk ofexperiencing adverse side effects, especially those that are associatedwith TASIGNA's food effect, as well as for a nilotinib treatment thatdoes not require such restricted co-administration of nilotinib with agastric acid-reducing agent.

SUMMARY OF DISCLOSURE

An aspect of the disclosure relates to an amorphous solid dispersion(“ASD”) comprising nilotinib. The ASD comprises nilotinib and one ormore polymers. In some embodiments, the ASD comprises nilotinib and oneor more polymers that exhibits pH-dependent solubility.

In another aspect, the disclosure provides pharmaceutical compositionscomprising the ASDs. In particular, the disclosure provides apharmaceutical composition in the form of an orally disintegratingtablet. The pharmaceutical composition comprises an ASD of nilotinib andone or more pharmaceutically acceptable excipients.

In another aspect, the disclosure provides pharmaceutical compositionsthat are effectively bioequivalent to a suitable reference compositionwhen administered to healthy human subjects in a fasted state, but at alower molar dose of the active ingredient as compared to the referencecomposition. In some embodiments, the reference composition is aconventional immediate-release nilotinib composition comprisingnilotinib monohydrochloride monohydrate. In some embodiments, thereference composition is a conventional immediate-release nilotinibcomposition comprising nilotinib monohydrochloride monohydrate incrystalline form. In some embodiments, the reference composition is incapsule form. In some embodiments, the reference composition is TASIGNAIR Capsules.

Yet another aspect of the disclosure relates to a method of treating adisease which responds to an inhibition of protein kinase activity, suchas a proliferative disorder. In some embodiments, the method comprisesadministration of an ASD or pharmaceutical composition of the presentdisclosure to a patient. In some embodiments, the composition isadministered without regard to consumption of food. In some embodiments,the composition is administered without regard to whether the patient isin a fasted state or a fed state.

In another embodiment, the disclosure provides a method of safelydelivering nilotinib to a patient in need thereof, the methodcomprising: (a) administering to the patient a therapeutically effectiveamount of a pharmaceutical composition of the disclosure; and (b)administering a meal to the patient; wherein steps (a) and (b) occurwithin less than two hours of each other.

In other embodiments, the disclosure provides kits for sale to a user.The kits comprise a pharmaceutical composition according to thedisclosure, and a package insert. The package insert informs the user ofthe proper use of the pharmaceutical composition. In one embodiment, thepackage insert informs the user that the pharmaceutical composition canbe administered with food. In another embodiment, the package insertinforms the user that the pharmaceutical composition can be administeredwith or without food. In another embodiment, the package insert does notinclude a warning that the pharmaceutical composition should not beadministered with food.

DETAILED DESCRIPTION

The present disclosure is related to technology described and disclosedin U.S. Provisional App. No. 62/968,749 (filed Jan. 31, 2020) which ishereby incorporated by reference in its entirety. The present disclosureis also related to technology described and disclosed in U.S.Provisional App. No. 63/018,213 (filed Apr. 30, 2020) which is herebyincorporated by reference in its entirety. The present disclosure isalso related to technology described and disclosed in U.S. ProvisionalApp. No. 63/067,064 (filed Aug. 18, 2020) which is hereby incorporatedby reference in its entirety. The present disclosure is also related totechnology described and disclosed in U.S. Provisional App. No.63/122,751 (filed Dec. 8, 2020) which is hereby incorporated byreference in its entirety. The present disclosure is also related totechnology described and disclosed in PCT/US 2021/15864 (filed Jan. 29,2021) which is hereby incorporated by reference in its entirety.

The present disclosure relates to pharmaceutical compositions comprisingnilotinib ASDs, and methods of treatment comprising administration ofthe pharmaceutical compositions. In one aspect, the present disclosureprovides a pharmaceutical composition in the form of an orallydisintegrating tablet.

The nilotinib ASDs and the pharmaceutical compositions of the presentdisclosure may provide particular advantages over conventionalimmediate-release crystalline nilotinib formulations, such as TASIGNA.For instance, as described herein, the prescribing information forTASIGNA warns to avoid food 2 hours before and 1 hour after taking adose. In contrast, certain ASDs and pharmaceutical compositions of thepresent disclosure can be administered without regard to foodconsumption.

Moreover, certain ASDs and pharmaceutical compositions of the presentdisclosure unexpectedly provide a pharmacokinetic profile similar tothat of TASIGNA, even when the dose of nilotinib administered by thepharmaceutical compositions is a fraction of the dose of nilotinibnormally administered when using TASIGNA. Therefore, the disclosureprovides pharmaceutical compositions that can be administered at a lowerdose than TASIGNA, but that would be expected to provide a comparabletherapeutic effect.

As another advantage, pharmaceutical compositions of the disclosure mayachieve a reduced inter-subject and/or intra-subject variability, ascompared to the variability observed for TASIGNA.

In addition, the pharmaceutical compositions of the present disclosureovercome the challenges faced by patients who have difficulty swallowingan intact solid oral dosage form, by providing an orally disintegratingtablet that disintegrates within 40 seconds or less, or more suitably,within 30 seconds or less. This orally disintegrating tablet may beparticularly beneficial for geriatric or pediatric patients, or patientssuffering from dysphagia for any reason.

Thus, the ASDs and the pharmaceutical compositions of the presentdisclosure may offer a safer but equally effective presentation ofnilotinib as compared to the currently available immediate-releaseproduct.

Nilotinib

Nilotinib is a kinase inhibitor having the following structure:

The chemical name for nilotinib is4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzamide.The molecular formula is C₂₈H₂₂F₃N₇O, which corresponds to a molecularweight of 529 g/mol (nilotinib base, anhydrous).

Nilotinib is marketed under the tradename TASIGNA, as animmediate-release formulation containing nilotinib monohydrochloridemonohydrate. It is thought that the nilotinib monohydrochloridemonohydrate in TASIGNA is in a crystalline form. Currently availableTASIGNA capsules (marketed in the United States under New DrugApplication 22-068) are labeled as containing 50 mg, 150 mg, or 200 mgnilotinib base, anhydrous (equivalent to 55 mg, 166 mg, and 221 mgnilotinib monohydrochloride monohydrate, respectively.) As used herein,“TASIGNA IR Capsule” refers to commercially available TASIGNAimmediate-release capsules.

Nilotinib monohydrochloride monohydrate is characterized as a Class IVcompound (low/moderate aqueous solubility and low permeability)according to the Biopharmaceutical Classification System (“BCS”). Apreparation of nilotinib in a form that is intended to enhance itssolubility could increase its bioavailability. One approach forenhancing solubility is to produce an amorphous solid dispersion.

Amorphous Solid Dispersions of Nilotinib

One aspect of the present disclosure relates to amorphous soliddispersions (“ASDs”) comprising nilotinib and one or more polymers. Apharmaceutically suitable amorphous solid dispersion generally comprisesa pharmaceutically active ingredient, such as nilotinib, dispersed in apharmacologically inert carrier, such as a polymer. One aim of apharmaceutically suitable amorphous solid dispersion is to improve thebioavailability of the pharmaceutically active ingredient. Thisimprovement can occur, for example, because of enhanced surface area,improved wettability or dispersibility, increased dissolution rate, orother factors.

In general, it is favorable if the pharmaceutically active ingredient isdispersed in the polymer to form what has been termed in the art as a“glass solution.” However, other forms of dispersion, such as thosetermed as “solid solution” or “glass suspension,” may also be suitable.The precise characterization of the solid dispersion is not important,provided that the amorphous solid dispersion is capable of providingdesired characteristics and performance.

In the ASDs of the disclosure, the nilotinib may be as a free base or asa salt such as a hydrochloride. In some embodiments, the nilotinib is asa free base and is anhydrous. Such forms of nilotinib and processes ofpreparing nilotinib are disclosed, for example, in WO 2004/005281 and WO2007/015871. In the description of the amorphous solid dispersions andpharmaceutical compositions below, and in the claims, any reference to“nilotinib” refers broadly to nilotinib free base, salts of nilotinib,anhydrous nilotinib (or salts thereof), hydrates or solvates ofnilotinib, and hydrates or solvates of nilotinib salts as suitablealternatives, unless specified.

The one or more polymers, which should be pharmacologically inert,should be suitable to provide structure and stability to the ASD. By“pharmacologically inert,” it is meant that the material does notinitiate a pharmacological response or an adverse reaction whenintroduced to a relevant biological system (such as the gastrointestinaltract).

In some embodiments, the ASD comprises nilotinib and one or morepolymers. In certain embodiments, the ASD consists of nilotinib and theone or more polymers. In certain other embodiments, the ASD consistsessentially of nilotinib and the one or more polymers.

Polymers that can be used in the ASDs of the present disclosure mayinclude, but are not limited to, those described below. The term“polymer” includes, but is not limited to, organic homopolymers,copolymers (such as for example, block, graft, random, and terpolymers,etc.), and blends and modifications thereof. The term “copolymer” refersto polymers containing two or more different monomeric units orsegments, and includes terpolymers, tetrapolymers, etc. Informationregarding suitable polymers, and commercial sources therefor, can befound in Sheskey P J (ed.) Handbook of Pharmaceutical Excipients, 9^(th)Ed. London: Pharmaceutical Press; 2020 (ISBN 0857113755); alternatively,the most up-to-date edition of the same title may be consulted.

Polymers that can be used in the ASDs of the present disclosure mayinclude ionizable or non-ionizable polymers, or a combination thereof.

In some embodiments, the one or more polymers may be non-ionizablepolymers. In certain embodiments, the ASD consists of nilotinib and oneor more non-ionizable polymers. In certain other embodiments, the ASDconsists essentially of nilotinib and one or more non-ionizablepolymers.

In some embodiments, the one or more polymers may be ionizable polymers.In certain embodiments, the ASD consists of nilotinib and one or moreionizable polymers. In certain other embodiments, the ASD consistsessentially of nilotinib and one or more ionizable polymers.

In yet other embodiments, a combination of ionizable and non-ionizablepolymers may be used. In certain embodiments, the ASD consists ofnilotinib and a combination of one or more non-ionizable polymers andone or more ionizable polymers. In certain other embodiments, the ASDconsists essentially of nilotinib and a combination of one or morenon-ionizable polymers and one or more ionizable polymers.

Polymers that can be used in the ASDs of the present disclosure mayinclude polymers that exhibit pH-dependent solubility, or polymers thatare generally insensitive to pH, or a combination thereof.

In some embodiments, the one or more polymers may exhibit pH-dependentsolubility. In certain embodiments, the ASD consists of nilotinib andone or more polymers that exhibits pH-dependent solubility. In certainother embodiments, the ASD consists essentially of nilotinib and one ormore polymers that exhibits pH-dependent solubility.

In other embodiments, the one or more polymers may be generallyinsensitive to pH. In certain embodiments, the ASD consists of nilotiniband one or more polymers generally insensitive to pH. In certain otherembodiments, the ASD consists essentially of nilotinib and one or morepolymers generally insensitive to pH.

In yet other embodiments, a combination of polymers may include one ormore polymers exhibiting pH-dependent solubility and one or morepolymers generally insensitive to pH. In certain embodiments, the ASDconsists of nilotinib and a combination of one or more polymersexhibiting pH-dependent solubility and one or more polymers generallyinsensitive to pH. In certain other embodiments, the ASD consistsessentially of nilotinib and a combination of one or more polymersexhibiting pH-dependent solubility and one or more polymers generallyinsensitive to pH.

Non-ionizable polymers. Suitable non-ionizable polymers may include:polysaccharides and polysaccharide derivatives (including celluloseethers and non-ionizable cellulose esters); polymers or copolymers ofN-vinylpyrrolidone and/or vinyl acetate; polymers of ethylene oxide;homopolymers or copolymers of lactic acid and/or glycolic acid; maleicanhydride copolymers; polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer; and poloxamers.

Suitable non-ionizable polysaccharides and polysaccharide derivativesmay include cellulose ethers and non-ionizable cellulose esters.Examples of suitable cellulose ethers include methylcellulose (“MC”;e.g., METHOCEL A15 LV, METHOCEL A4M), ethylcellulose (“EC”; e.g.,ETHOCEL), hypromellose or hydroxypropyl methylcellulose (“HPMC”; e.g.,METHOCEL E3, METHOCEL E5, METHOCEL E6, METHOCEL E15, AFFINISOL HPMCHME), hydroxyethyl cellulose (“HEC”; e.g., NATROSOL 250 Pharm), andhydroxypropyl cellulose (“HPC”; e.g., HPC EF, HPC LF, HPC JF, HPC L,KLUCEL).

Examples of non-ionizable cellulose esters that may be suitable includecellulose acetate, cellulose propionate, cellulose butyrate, andcellulose acetate butyrate.

Examples of suitable polymers or copolymers of N-vinylpyrrolidone and/orvinyl acetate include polyvinylpyrrolidone (“PVP”; e.g., PVP K25, PVPK90, VIVAPHARM PVP), crospovidone or crosslinked polyvinylpyrrolidone(e.g., KOLLIDON CL, VIVAPHARM PVPP), copovidone orvinylpyrrolidone/vinyl acetate copolymer (“PVP/VA”; e.g., KOLLIDON VA64, VIVAPHARM PVP/VA 64), and polyvinyl alcohol (“PVA”; e.g., VIVAPHARMPVA).

Examples of suitable polymers of ethylene oxide include polyethyleneglycol (“PEG”; e.g., KOLLISOLV PEG 8000) and poly(ethylene oxide)(“PEO”; e.g., POLYOX).

Examples of suitable homopolymers or copolymers of lactic acid and/orglycolic acid include polylactide or poly(lactic acid) (“PLA”),polyglycolide or poly(glycolic acid) (“PGA”), andpoly(lactic-co-glycolic acid) (“PLGA”).

Non-ionizable maleic anhydride copolymers such as poly(methyl vinylether/maleic anhydride) (“PVM/MA”) may also be suitable. Non-ionizablepoloxamers (e.g., PLURONIC, KOLLIPHOR) may also be suitable.

A polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graftcopolymer (e.g., SOLUPLUS) may also be a suitable non-ionizable polymer.

Ionizable polymers. Suitable ionizable polymers may be considered“anionic” or “cationic” polymers. Anionic and cationic polymers oftenexhibit pH-dependent solubility.

Anionic polymers often include carboxylate (such as acetate), phthalate,succinate, or acrylate functionalities. Anionic polymers are generallyinsoluble at low pH and more soluble at higher pH. Suitable anionicpolymers may include anionic polysaccharides and polysaccharidederivatives (such as ionizable cellulose esters), copolymers ofmethacrylic acid and/or alkyl acrylate, and derivatized vinyl acetatepolymers, for example.

An example of an ionizable polysaccharide that may be suitable isxanthan gum. Examples of suitable ionizable cellulose esters may includecarboxymethylcellulose (“CMC”; carboxymethylcellulose sodium),hypromellose acetate succinate, or hydroxypropyl methylcellulose acetatesuccinate (“HPMC-AS”; e.g., AFFINISOL HPMC-AS, AQUASOLVE, AQOAT),hydroxypropyl methylcellulose phthalate (“HPMC-P”; e.g., HP-50, HP-55),and cellulose acetate phthalate (“CAP”; e.g., EASTMAN C-A-P).

Suitable copolymers of methacrylic acid and/or alkyl methacrylate mayinclude methacrylic acid/methyl methacrylate copolymer (e.g., EUDRAGITL100) and methacrylic acid/ethyl acrylate copolymer (e.g., EUDRAGITL100-55, KOLLICOAT MAE).

An example of a derivatized vinyl acetate polymer that may be suitableis polyvinyl acetate phthalate (PVA-P; PHTHALAVIN).

Cationic polymers often include amine functionalities. Cationic polymersare generally soluble at low pH and less soluble at higher pH. Suitablecationic polymers may include cationic polysaccharides andpolysaccharide derivatives, and amine-functionalized copolymers ofmethacrylic acid and/or alkyl acrylate, for example.

An example of a cationic polysaccharide that may be suitable ischitosan.

Suitable amine-functionalized copolymers of methacrylic acid and/oralkyl acrylate include, for example, dimethylaminoethylmethacrylate/butyl methacrylate/methyl methacrylate copolymer (e.g.,EUDRAGIT E100) and aminoalkyl methacrylate copolymer such as poly(ethylacrylate-co-methyl methacrylate-co-trimethylammonioethyl methacrylatechloride (e.g., EUDRAGIT RL100, EUDRAGIT RL PO, EUDRAGIT RS PO).

In some embodiments, the one or more polymers comprise polymers that arecharacterized by pH-dependent solubility. In some embodiments, the oneor more polymers comprise an anionic polymer characterized bypH-dependent solubility. In some embodiments, the one or more polymersconsist essentially of one or more anionic polymers characterized bypH-dependent solubility. In some embodiments, the one or more polymersconsist of one or more anionic polymers characterized by pH-dependentsolubility.

HPMC-AS and EUDRAGIT L100-55 are examples of suitable anionic polymersthat demonstrate pH-dependent solubility, but other polymers thatdemonstrate pH-dependent solubility may also be employed.

In certain embodiments, the one or more polymers comprise HPMC-AS. Incertain embodiments, the polymer consists of HPMC-AS. In certainembodiments, the polymer consists essentially of HPMC-AS.

HPMC-AS is available in a variety of grades, which each demonstratepH-dependent aqueous solubility. Generally speaking, HPMC-AS is largelyinsoluble in an aqueous medium at pH of 4 or lower, and largely solublein an aqueous medium at pH 7 or greater. It is insoluble in normalgastric fluid, but swells and dissolves in the higher pH environment ofthe upper small intestine. The grades of HPMC-AS are differentiated bythe relative proportion of acetyl/succinyl substituents. Low-gradeHPMC-AS comprises 5-9% acetyl substituents and 14-18% succinylsubstituents; mid-grade HPMC-AS comprises 7-11% acetyl substituents and10-14% succinyl substituents; high-grade HPMC-AS comprises 10-14% acetylsubstituents and 4-8% succinyl substituents. In the practice of thedisclosure, any grade of HPMC-AS may be suitable, or a mixture of two ormore grades may be suitable. In certain embodiments, mid-grade HPMC-ASis particularly suitable.

In certain embodiments, the ASD consists of nilotinib and HPMC-AS. Incertain embodiments, the ASD consists essentially of nilotinib andHPMC-AS. In certain embodiments, the ASD consists of anhydrous, freebase nilotinib and HPMC-AS. In certain embodiments, the ASD consistsessentially of anhydrous, free base nilotinib and HPMC-AS. In certainembodiments, the ASD consists of nilotinib and mid-grade HPMC-AS. Incertain embodiments, the ASD consists essentially of nilotinib andmid-grade HPMC-AS. In certain embodiments, the ASD consists ofanhydrous, free base nilotinib and mid-grade HPMC-AS. In certainembodiments, the ASD consists essentially of anhydrous, free basenilotinib and mid-grade HPMC-AS.

In some embodiments, the one or more polymers comprise a copolymer ofmethacrylic acid and/or alkyl methacrylate. In some embodiments, the oneor more polymers comprise methacrylic acid/methyl methacrylate copolymer(e.g., EUDRAGIT L100) or methacrylic acid/ethyl acrylate copolymer(e.g., EUDRAGIT L100-55).

In some embodiments, the one or more polymers comprise methacrylicacid/ethyl acrylate copolymer. In certain embodiments, the polymerconsists of methacrylic acid/ethyl acrylate copolymer. In certainembodiments, the polymer consists essentially of methacrylic acid/ethylacrylate copolymer.

In some embodiments, the ASD comprises nilotinib and methacrylicacid/ethyl acrylate copolymer. In certain embodiments, the ASD consistsof nilotinib and methacrylic acid/ethyl acrylate copolymer. In certainother embodiments, the ASD consists essentially of nilotinib andmethacrylic acid/ethyl acrylate copolymer. In certain embodiments, theASD comprises anhydrous, free base nilotinib and methacrylic acid/ethylacrylate copolymer. In certain embodiments, the ASD consists ofanhydrous, free base nilotinib and methacrylic acid/ethyl acrylatecopolymer. In certain embodiments, the ASD consists essentially ofanhydrous, free base nilotinib and methacrylic acid/ethyl acrylatecopolymer.

In any of the foregoing, the methacrylic acid/ethyl acrylate copolymercan be EUDRAGIT L100-55, for example. EUDRAGIT L100-55 is an anioniccopolymer demonstrating pH-dependent aqueous solubility. Generallyspeaking, EUDRAGIT L100-55 is largely insoluble in an aqueous medium atpH of 5 or lower, and largely soluble in an aqueous medium at pH 5.5 orgreater.

In some embodiments of the ASD, the one or more polymers does notcomprise a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft co-polymer (e.g., SOLUPLUS). In some embodiments, the ASD issubstantially free from a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft co-polymer. In some embodiments, theASD is essentially free from a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft co-polymer. In some embodiments, theASD is free from a polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft co-polymer. In yet other embodiments, the ASD comprisesnilotinib and one or more polymers, with the proviso that the one ormore polymer is not a polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft co-polymer.

In some embodiments of the ASD, the one or more polymers does notcomprise a poloxamer. In some embodiments, the ASD is substantially freefrom a poloxamer. In some embodiments, the ASD is essentially free froma poloxamer. In some embodiments, the ASD is free from a poloxamer. Inyet other embodiments, the ASD comprises nilotinib and one or morepolymers, with the proviso that the one or more polymer is not apoloxamer.

In some embodiments of the ASD, the one or more polymers does notcomprise an anionic polymer comprising phthalate functionalities. Insome embodiments, the ASD is substantially free from an anionic polymercomprising phthalate functionalities. In some embodiments, the ASD isessentially free from an anionic polymer comprising phthalatefunctionalities. In some embodiments, the ASD is free from an anionicpolymer comprising phthalate functionalities. In yet other embodiments,the ASD comprises nilotinib and one or more polymers, with the provisothat the one or more polymer is not an anionic polymer comprisingphthalate functionalities.

In some embodiments of the ASD, the one or more polymers does notcomprise a hydroxypropyl methylcellulose phthalate. In some embodiments,the ASD is substantially free from a hydroxypropyl methylcellulosephthalate. In some embodiments, the ASD is essentially free from ahydroxypropyl methylcellulose phthalate. In some embodiments, the ASD isfree from a hydroxypropyl methylcellulose phthalate. In yet otherembodiments, the ASD comprises nilotinib and one or more polymers, withthe proviso that the one or more polymer is not a hydroxypropylmethylcellulose phthalate.

In some embodiments of the ASD, the one or more polymers does notcomprise a polyvinyl acetate phthalate. In some embodiments, the ASD issubstantially free from a polyvinyl acetate phthalate. In someembodiments, the ASD is essentially free from a polyvinyl acetatephthalate. In some embodiments, the ASD is free from a polyvinyl acetatephthalate. In yet other embodiments, the ASD comprises nilotinib and oneor more polymers, with the proviso that the one or more polymer is not apolyvinyl acetate phthalate.

In some embodiments of the ASD, the one or more polymers does notcomprise a polymer or copolymer of N-vinylpyrrolidone. In someembodiments, the ASD is substantially free from a polymer or copolymerof N-vinylpyrrolidone. In some embodiments, the ASD is essentially freefrom a polymer or copolymer of N-vinylpyrrolidone. In some embodiments,the ASD is free from a polymer or copolymer of N-vinylpyrrolidone. Inyet other embodiments, the ASD comprises nilotinib and one or morepolymers, with the proviso that the one or more polymer is not a polymeror copolymer of N-vinylpyrrolidone. In the foregoing, the polymer orcopolymer of N-vinylpyrrolidone can be polyvinylpyrrolidone,crospovidone or crosslinked polyvinylpyrrolidone, copovidone orvinylpyrrolidone/vinyl acetate copolymer.

As used herein, the phrase “substantially free from” means that thestated component represents not more than 10% of the ASD, based onweight. The phrase “essentially free from” means that the statedcomponent represents not more than 5% of the ASD, based on weight. Theterm “free from” means that the stated component represents not morethan 2% of the ASD, based on weight.

In the ASDs described in the disclosure, the amount of nilotinib ascompared to the amount of the one or more polymers may vary. Forexample, nilotinib and the one or more polymers may be present in a w/wratio (nilotinib:polymer) of 20:80 to 95:5. In certain embodiments,nilotinib and the one or more polymers may be present in a w/w ratio of25:75 to 90:10, or 30:70 to 85:15, or 35:65 to 80:20. In someembodiments, nilotinib and the one or more polymers may be present in aw/w ratio of 40:60 to 70:30, such as 40:60, or 45:55, or 50:50, or55:45, or 60:40, or 65:35, or 70:30. In particular embodiments, the w/wratio is 20:80, 25:75, 30:70, 35:65, 40:60, 45:55, 50:50, 55:45, 60:40,65:35, 70:30, 75:25, 80:20, 85:15, 90:10, or 95:5.

In some embodiments, the ASD consists of nilotinib and one or morepolymers. In some embodiments, the ASD consists essentially of nilotiniband one or more polymers. In other embodiments, the ASDs of the presentdisclosure may additionally comprise one or more other pharmaceuticallyacceptable functional components, such as one or more antioxidants,wetting agents, or solubilizers.

As used herein, the phrase “pharmaceutically acceptable” means that thecomponent does not initiate a pharmacological response or an adversereaction when introduced to a relevant biological system. By way ofnon-limiting example only, a substance found in the U.S. Food & DrugAdministration's “Generally Recognized as Safe” (“GRAS”) list, or asubstance used in accordance with guidelines in its Inactive IngredientDatabase, would be considered pharmaceutically acceptable. Similarly, asubstance in a corresponding database or list maintained by a parallelregulatory body, such as the European Medicines Agency, would beconsidered pharmaceutically acceptable. In general, in thepharmaceutical compositions of the disclosure, it is desirable to employonly components that do not cause an unacceptable level of physical orchemical instability in the resulting composition.

Examples of antioxidants that may be used in the ASDs of the presentdisclosure include, but are not limited to, acetylcysteine, ascorbylpalmitate, butylated hydroxyanisole (“BHA”), butylated hydroxytoluene(“BHT”), monothioglycerol, potassium nitrate, sodium ascorbate, sodiumformaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite,vitamin E or a derivative thereof, propyl gallate,ethylenediaminetetraacetic acid (“EDTA”) (e.g., disodium edetate),diethylenetriaminepentaacetic acid (“DTPA”), bismuth sodiumtriglycollamate, or a combination thereof. Antioxidants may alsocomprise amino acids such as methionine, histidine, cysteine and thosecarrying a charged side chain, such as arginine, lysine, aspartic acid,and glutamic acid. Any stereoisomer (e.g., l-, d-, or a combinationthereof) of any particular amino acid (e.g., methionine, histidine,arginine, lysine, isoleucine, aspartic acid, tryptophan, threonine andcombinations thereof) or combinations of these stereoisomers, may bepresent so long as the amino acid is present either in its free baseform or its salt form.

In some embodiments, the one or more antioxidants comprise BHT. In someembodiments, the one or more antioxidants consists of BHT.

The one or more antioxidants may be present in the ASD in an amount of0.001% to 2%, or 0.01% to 1.5%, or 0.05% to 1%, or 0.1% to 0.5%, or 0.3%to 0.4%, by weight. Examples of the amount of the one or moreantioxidants in the ASD include 0.001%, or 0.003%, or 0.005%, or 0.008%,or 0.01%, or 0.015%, or 0.02%, or 0.025%, or 0.03%, or 0.035%, or 0.04%,or 0.05%, or 0.075%, or 0.1%, or 0.2%, or 0.3%, or 0.4%, or 0.5%, or0.75%, or 1%, or 1.5%, or 2%, by weight.

A variety of pharmaceutically acceptable wetting agents may be included.As a non-limiting example of a wetting agent, poloxamers, such aspoloxamer 407 (e.g., PLURONIC F-127) or poloxamer 188 (e.g., PLURONICF-68), may be suitable. Other known pharmaceutically acceptable wettingagents may be suitably employed. A wetting agent may be included in theASD in an amount of 0.5% to 10%, or 1% to 8%, or 2% to 6%, by weight.

A variety of pharmaceutically acceptable solubilizers may be included.Non-limiting examples of suitable solubilizers include vitamin E TPGS(D-α-tocopherol polyethylene glycol succinate), sodium lauryl sulfate(“SLS”), and docusate sodium. Other known pharmaceutically acceptablesolubilizers may be suitably employed. A solubilizer may be included inthe ASD in an amount of 0.1% to 10%, or 0.25% to 5%, or 0.5 to 1%, byweight.

In some embodiments, the ASD comprises nilotinib, one or more polymers,and one or more antioxidants. In certain embodiments, the ASD consistsessentially of nilotinib, one or more polymers, and one or moreantioxidants. In certain embodiments, the ASD consists of nilotinib, oneor more polymers, and one or more antioxidants.

In some embodiments, the ASD comprises nilotinib, HPMC-AS, and BHT. Incertain embodiments, the ASD consists essentially of nilotinib, HPMC-AS,and BHT. In certain embodiments, the ASD consists of nilotinib, HPMC-AS,and BHT. In some embodiments, the ASD comprises nilotinib, mid-gradeHPMC-AS, and BHT. In certain embodiments, the ASD consists essentiallyof nilotinib, mid-grade HPMC-AS, and BHT. In certain embodiments, theASD consists of nilotinib, mid-grade HPMC-AS, and BHT.

In particular embodiments, the ASD consists essentially of nilotinib andHPMC-AS at a ratio of 50:50, and BHT in at a level of 0.1-0.5% by weightof the ASD. In particular embodiments, the ASD consists of nilotinib andHPMC-AS at a ratio of 50:50, and BHT in at a level of 0.1-0.5% by weightof the ASD.

In some embodiments, the ASD comprises nilotinib, methacrylic acid/ethylacrylate copolymer (such as EUDRAGIT L100-55), and BHT. In certainembodiments, the ASD consists essentially of nilotinib, a methacrylicacid/ethyl acrylate copolymer, and BHT. In certain embodiments, the ASDconsists of nilotinib, methacrylic acid/ethyl acrylate copolymer, andBHT.

In particular embodiments, the ASD consists essentially of nilotinib,methacrylic acid/ethyl acrylate copolymer (such as EUDRAGIT L100-55),and BHT at a level of 0.1-0.5%, by weight of the ASD. In particularembodiments, the ASD consists of nilotinib, methacrylic acid/ethylacrylate copolymer, and BHT at a level of 0.1-0.5%, by weight of theASD.

The drug load of nilotinib in the ASDs of the present disclosure maysuitably range from 20% to 95%, or 25% to 90%, or 30% to 80%, or 35% to70%, or 40% to 60%, or 45% to 55%. As used herein, the phrase “drugload” refers to the ratio (by weight %) of nilotinib in an ASD to thetotal solids weight of the ASD. By way of example, for an ASD consistingof nilotinib and a polymer, a 1:1 w/w ratio of nilotinib:polymer wouldrepresent a 50% drug load; a 1:2 w/w ratio of nilotinib:polymer wouldrepresent a 33.3% drug load, etc. Examples of the drug load of nilotinibin specific embodiments of the ASDs include 20%, or 25%, or 30%, or 35%,or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or 75%, or 80%,or 85%, or 90%.

The nilotinib ASDs may be in the form of particles. In some embodiments,the particles do not comprise a surfactant. In other embodiments, theparticles do not comprise a wetting agent. In other embodiments, theparticles do not comprise a solubilizer. In other embodiments, theparticles comprise neither a surfactant nor a solubilizer. In otherembodiments, the particles are free from surfactants, wetting agents,and solubilizers. In other embodiments, the particles consist of polymerand nilotinib, and no additional functional components. In certainembodiments, the particles consist of polymer, nilotinib, one or moreantioxidants, and no additional functional components.

Particles of the ASDs of the disclosure may generally comprise theshapes of spheroids. As measured by conventional light scattering orlaser diffraction techniques, the diameter of the particles maygenerally range from 0.05 μm to 100 The median diameter (D50 or Dv0.5)of the particle distribution may be in the range from 0.2 μm to 60 or0.5 μm to 50 or 0.5 μm to 40 μm.

In some embodiments, the median diameter of the particle distributionmay be from 1 μm to 40 μm, or from 2 μm to 25 μm, or from 3 μm to 20 μm.By way of example only, such particle size distributions can be achievedby known methods of spray drying.

In some embodiments, the median diameter of the particle distributionmay be from 0.1 μm to 10 μm, or from 0.2 μm to 5 μm, or from 0.5 μm to 2μm. By way of example only, such particle size distributions can beachieved by methods involving electrospraying, discussed further below.

The nilotinib ASDs of the present disclosure may demonstrate a desirablelevel of physical and/or chemical stability, which can be assessed bydifferent measures. Stability is generally assessed using conventionalanalytical techniques commonly known in pharmaceutical sciences.

Physical and chemical stability is generally assessed after storageunder controlled, elevated environmental conditions (“acceleratedconditions”) over a specified period of time. The storage conditions maybe one or more of 25° C./60% relative humidity (“RH”), or 25°C./protected, or 30° C./65% RH, or 40° C./75% RH, or 40° C./protected,or 50° C./80% RH. (As used herein in this context, “protected” meanssamples were sealed in foil pouches and placed in a controlled chamberfor the storage period). The period of time may be one or more of 1week, or 2 weeks, or 4 weeks or 1 month, or 2 months, or 3 months, or 4months, or 6 months, or 9 months, or 12 months, or 15 months, or 18months, or 21 months, or 24 months, or any period of time therebetween.

The nilotinib ASDs may demonstrate stability by having a particularassay value or a particular level of total related substances (e.g.,impurities), as measured by high performance liquid chromatography(“HPLC”), after storage under accelerated conditions over a specifiedperiod of time. The assay value is generally presented as a percentageof the quantity of analyte (e.g., nilotinib) detected relative to thequantity expected, where 100% is a favorable result and large deviationsfrom 100% are unfavorable. The total related substances is generallypresented as a percentage relative to the total quantity of substancesdetected (i.e., analyte plus impurities), where near 0% is favorable andlarge deviations from 0% are unfavorable.

In some embodiments, the nilotinib ASDs may have an assay as measured byHPLC of at least 90%, or at least 93%, or at least 95%, or at least 97%,or at least 98%, or at least 99%. In some embodiments, the nilotinibASDs may have a level of total related substances as measured by HPLC ofno more than 3%, no more than 2.5%, no more than 2%, or no more than1.5%, or no more than 1%, or no more than 0.9%, or no more than 0.8%, orno more than 0.7%, or no more than 0.6%, or no more than 0.5%.

In some embodiments, the nilotinib ASDs may have an assay as measured byHPLC of at least 90%, or at least 93%, or at least 95%, or at least 97%,or at least 98%, after storage at 25° C./60% RH for 1 month, or 2months, or 3 months, or 6 months, or 9 months, or 12 months; or afterstorage at 40° C./75% RH for 1 month, or 2 months, or 3 months, or 6months.

In some embodiments, the nilotinib ASDs may have a level of totalrelated substances as measured by HPLC of no more than 2%, or no morethan 1.5%, or no more than 1%, or no more than 0.9%, or no more than0.8%, or no more than 0.7%, or no more than 0.6%, or no more than 0.5%,after storage at 25° C./60% RH for 1 month, or 2 months, or 3 months, or6 months, or 9 months, or 12 months; or after storage at 40° C./75% RHfor 1 month, or 2 months, or 3 months, or 6 months.

Stability may also be assessed by evaluating changes in glass transitiontemperature of the nilotinib ASDs under different storage conditionsover time. Glass transition temperature can be evaluated by modulatedDSC (“mDSC”) using conventional techniques. In some embodiments, the ASDis characterized by a single glass transition, the transition observedin the range from 25° C. to 200° C., or more suitably from 40° C. to150° C., by DSC or mDSC. In other embodiments, the ASD is characterizedby more than one transition, the transitions observed in the range from25° C. to 200° C., or more suitably from 40° C. to 150° C., by DSC ormDSC.

In some embodiments, the glass transition temperature as measured bymDSC does not change by more than 5° C., or more than 4° C., or no morethan 3° C., or no more than 2° C., after storage at 25° C./60% RH for 1month, or 2 months, or 3 months, or 6 months, or 9 months, or 12 months.In some embodiments, the glass transition temperature as measured bymDSC does not change by more than 6° C., or more than 5° C., or morethan 4° C., or more than 3° C., or more than 2° C., or no more than 1°C., after storage at 40° C./75% RH for 1 month, or 2 months, or 3months, or 6 months.

Further, stability may be assessed by evaluating changes incrystallinity of the nilotinib ASDs under different storage conditionsover time, such as by suitable conventional x-ray diffraction (“XRD”)techniques (also known in the art as powder XRD or PXRD). In thepractice of the present disclosure, it is preferred (but not required)that the nilotinib ASDs remain amorphous or essentially amorphous. Insome embodiments, “amorphous” may be defined as having no detectablecrystallinity as determined using methods known in the art, forinstance, by using XRD. An example of using XRD to determine amorphicityis provided in Example 1.

In some embodiments, “amorphous” may be defined as having a percentcrystallinity no more than 5%, or no more than 4%, or no more than 3%,or no more than 2%, or no more than 1%, as determined by XRD. In someembodiments, “essentially amorphous” may be defined as having a percentcrystallinity of no more than 8%, or no more than 7%, or no more than6%, as measured by XRD.

The ASDs of the disclosure may be amorphous or essentially amorphouswhen analyzed promptly after preparation, i.e., at t=0. For thesepurposes, the phrase “promptly after preparation” means that the ASD isanalyzed within a few days after preparation, and stored under protectedconditions at ambient temperature and humidity after preparation andbefore analysis.

The ASDs may be amorphous or essentially amorphous after storage undervarious storage conditions (e.g., 25° C./60% RH, 25° C./protected, 40°C./75% RH, 40° C./protected, 50° C./80% RH, etc.) for a period of atleast 1 week, or a period of at least 2 weeks, or a period of at least 3weeks, or a period of at least 4 weeks or 1 month, or a period of atleast 2 months, or a period of at least 3 months, or a period of atleast 4 months, or a period of at least 5 months, or a period of atleast 6 months, or a period of at least 9 months, or a period of atleast 12 months or 1 year. In some embodiments, the ASDs of thedisclosure may be amorphous or essentially amorphous under conditions ofhigh temperature and humidity (e.g., 40° C./75% RH) for a period of atleast 1 month, or a period of at least 2 months, or a period of at least3 months, or a period of at least 6 months.

The nilotinib ASDs of the present disclosure can be characterized forwater content, such as by using standard Karl Fischer coulometrictitration methods. In some embodiments, the nilotinib ASDs may comprisea water content as assessed by Karl Fischer coulometric titration methodof no more than 3%, or no more than 2.5%, or no more than 2%, or no morethan 1.5%, or no more than 1%.

In some embodiments, the nilotinib ASDs may comprise a water content asassessed by Karl Fischer coulometric titration method of no more than5%, or no more than 4.5%, or no more than 4%, or no more than 3.5%, orno more than 3%, or no more than 2.5%, or no more than 2%, after storageat 25° C./60% RH for 1 month, or 2 months, or 3 months, or 6 months, or9 months, or 12 months. In some embodiments, the nilotinib ASDs maycomprise a water content as assessed by Karl Fischer coulometrictitration method of no more than 8%, or no more than 7%, or no more than6%, or no more than 5%, or no more than 4.5%, or no more than 4%, or nomore than 3.5%, or no more than 3%, or no more than 2.5%, or no morethan 2%, after storage at 40° C./75% RH for 1 month, or 2 months, or 3months, or 6 months, or 9 months, or 12 months.

Methods of Making Amorphous Solid Dispersions

The nilotinib ASDs of the present disclosure may be prepared by avariety of methods known in the art. Suitable methods generally includemixing, dissolving, or compounding the nilotinib and the one or morepolymers and, if present, one or more other functional components (suchas antioxidants, wetting agents, surfactants, or solubilizers) tointegrate the various components. In the practice of the variousmethods, the nilotinib may be introduced as nilotinib free base, or as asalt of nilotinib, or as a solvate or hydrate of nilotinib.

Suitable methods are generally known in the art, and include kneading,co-grinding, melting, melt extrusion, melt agglomeration, dropping, andthe like. After the integration step, the material can be furtherprocessed by drying, grinding or crushing, sieving, etc.

In the practice of certain methods, nilotinib and the one or morepolymers (and other functional components, if present) may be mixed ordissolved with one or more solvents to provide a liquid feedstock.Suitable solvents may include, but are not limited to, water; analcohol, such as ethanol, methanol, propanol or isopropanol; an ether,such as ethyl ether or methyl tert-butyl ether; acetonitrile;tetrahydrofuran or methyl tetrahydrofuran; an acetate, such as methylacetate or ethyl acetate; a ketone, such as acetone or 2-butanone(methyl ethyl ketone, or “MEK”); toluene; ethyl formate; 1,4-dioxane;dimethylsulfoxide; N-methyl 2-pyrrolidone; volatile halogenated solventssuch as chloroform or dichloromethane; and combinations thereof. Themixing or dissolving of these contents may be by methods known in theart. For example, the contents may be mixed by manually mixing, or maybe mixed with a mixing device continuously, periodically, or acombination thereof. Examples of mixing devices may include, but are notlimited to, a magnetic stirrer, shaker, a paddle mixer, homogenizer, andany combination thereof.

After the nilotinib and the one or more polymers (and other functionalcomponents, if present) are mixed, the liquid feedstock may be formedinto an amorphous solid dispersion, such as through solvent evaporation,lyophilization, precipitation or co-precipitation, spray drying,electrospraying, supercritical fluid extraction, etc. These methods areknown and commonly understood in the art.

In certain embodiments of the disclosure, the liquid feedstock may beformed into an amorphous solid dispersion through electrospraying.Electrospraying, which has also been referred to as electrohydrodynamicatomization, has been used to produce amorphous solid dispersionparticles on a micron or sub-micron scale from suitable liquidfeedstocks.

In one suitable electrospraying technique, the liquid feedstock isemitted through one or more nozzles toward a substrate in the presenceof an electric potential applied between the nozzles and the substrate.The liquid feedstock experiences electrical shear stress due to theapplied potential. When the shear stress overcomes the surface tensionof the liquid feedstock, droplets are emitted from the tips of thenozzles.

Conditions are controlled such that a cone jet of droplets is emitted atthe tip of the nozzles. The droplets take on an electric charge andrepel one another, which prevents their coagulation and promotesself-dispersion. The charged droplets accelerate toward the substrate asa result of the applied electric field.

During the short flight path, the solvent “flashes off” from the chargeddroplets. This fast evaporation creates a situation in which the chargeddroplets shrink in size but increase in charge density. At a criticallimit, the droplets will break up into yet smaller droplets. Anessentially monodisperse population of fine droplets is ultimatelyproduced. The size of the droplets can range from sub-micron to severalmicrons.

The essentially complete evaporation of solvent from the chargeddroplets results in the formation of relatively uniform particles of thenon-volatile components from the liquid feedstock. The evaporationprocess occurs at a time-scale that does not permit crystallization ofthe non-volatile components. Additionally, evaporative coolingassociated with the extremely rapid solvent evaporation contributes aquenching effect to preserve the particles in an amorphous state.Furthermore, electrospray conditions can be selected and the system canbe configured such that the amorphous particles contain little residualsolvent.

In some embodiments of the disclosure, the liquid feedstock may beformed into an ASD using electrospray techniques and/or devices.Suitable methods and equipment are described, for example, in U.S. Pat.Nos. 6,746,869, 6,764,720, 7,279,322, 7,498,063, 7,951,428, 7,972,661,8,992,603, 9,040,816, 9,050,611, 9,108,217, 9,642,694, 10,562,048, U.S.Patent Publication No. 2014-0158787, U.S. Patent Publication No.2015-0190253, U.S. Patent Publication No. 2016-0038968, U.S. PatentPublication No. 2016-0175881, U.S. Patent Publication No. 2016-0235677,U.S. Patent Publication No. 2019-0193109, and U.S. Patent PublicationNo. 2020-0179963.

As noted above, by using an electrospray technique, the median diameterof the nilotinib ASD particle distribution may be from 0.1 μm to 10 μm,or from 0.2 μm to 5 μm, or from 0.5 μm to 2 μm. It should further benoted that the nilotinib in the amorphous particles is generally notconsidered to be solvated. Even where the liquid feedstock may have beenprepared using a solvate or hydrate form of nilotinib, the solvate orhydrate is understood to flash off with the other solvents, and theelectrosprayed amorphous particles comprise non-solvated nilotinib (suchas anhydrous nilotinib).

In some embodiments, the electrospray technique may be performed at roomtemperature. In certain embodiments, no heated air is used. In otherembodiments, the liquid feedstock is held at an elevated temperatureduring the electrospray process.

In some embodiments, the electrospray technique may be performed usingone or more capillary nozzles. In certain embodiments, the electrospraytechnique does not use pneumatic nozzles such as nozzles that rely onkinetic energy; pressure nozzles; rotary nozzles; or nozzles that relyon centrifugal energy; or ultrasonic nozzles such as nozzles that relyon acoustic energy. In some embodiments, the electrospray techniquegenerates a yield of over 85%, or over 90%, or over 95%, or over 98%.

In other embodiments, the liquid feedstock may be formed into an ASDthrough spray drying. Generally speaking, spray drying involves theatomization of a liquid feedstock into very small droplets within a hotdrying gas. The feedstock is pumped or otherwise propelled through anozzle or other atomizing apparatus to form droplets within a dryingchamber. Within the drying chamber, the droplets are exposed to anenvironment of the heated drying gas (usually flowing air or nitrogen),leading to flash drying of the droplets (by evaporative removal ofsolvent) and resultant production of solid particles. The driedparticles are collected, generally at an output port in the dryingchamber.

Various apparatus and methods of spray drying may be employed to form anASD of the disclosure. In the practice of the present disclosure, themedian diameter of the ASD particle distribution achieved by spraydrying may be from 1 μm to 40 or from 2 μm to 25 μm, or from 3 μm to 20μm.

In some embodiments, the process for forming an ASD does not require asecondary drying step, i.e., a drying step that occurs after theparticles are produced. In other embodiments, a secondary drying step isemployed to further remove most or all of the residual solvents. Thesecondary drying step can be done under suitable conditions that allowfor the removal of solvent but do not result in the recrystallization ofthe nilotinib. For example, a secondary drying step can be done below aglass transition temperature. A secondary drying step can also be doneat reduced pressure. A combination of elevated temperature and reducedpressure can also be used for a secondary drying step.

Pharmaceutical Compositions

An aspect of the present disclosure relates to pharmaceuticalcompositions comprising nilotinib ASD. The pharmaceutical compositionsof the present disclosure may be in a dosage form appropriate for oraladministration. In some embodiments, the pharmaceutical compositions maybe in the form of granules, or may be prepared as granules as anintermediate step to forming another oral dosage form, such as tablets,sprinkles, or pellets. In some embodiments, the pharmaceuticalcompositions may be in a solid dosage form for oral administration, suchas a capsule, tablet, sprinkle, or pellet. The pharmaceuticalcomposition may also be in the form of an aqueous or nonaqueoussuspension or solution. Such compositions may be prepared using knownexcipients and known preparation methods.

In particular, in one aspect the present disclosure provides apharmaceutical composition in the form of an orally disintegratingtablet, discussed separately below.

In some forms, the pharmaceutical compositions may comprise a nilotinibASD of the present disclosure and one or more pharmaceuticallyacceptable excipients, such as one or more solubilizers, one or morebuffering agent(s), one or more pH-adjusting agents, one or moresurfactants, one or more antioxidants, and/or one or more carriers.Pharmaceutical compositions in the form of solid oral dosage forms mayalso comprise one or more fillers, one or more binders, one or morelubricants, one or more disintegrants, and/or other conventionalexcipients such as one or more glidants, for example.

Information regarding suitable excipients, and commercial sourcestherefor, can be found in Sheskey P J (ed.) Handbook of PharmaceuticalExcipients, 9^(th) Ed. London: Pharmaceutical Press; 2020 (ISBN0857113755); alternatively, the most up-to-date edition of the sametitle may be consulted.

The pharmaceutical compositions of the present disclosure may beprepared using methods known in the art. For example, the nilotinib ASDand the one or more pharmaceutically acceptable additives may be mixedby simple mixing, or may be mixed with a mixing device continuously,periodically, or a combination thereof. Examples of mixing devices mayinclude, but are not limited to, a magnetic stirrer, shaker, a paddlemixer, homogenizer, and any combination thereof.

Solubilizers that may be used in the pharmaceutical compositions of thepresent disclosure include, but are not limited to, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol copolymer (SOLUPLUS),d-α-tocopherol acid polyethylene glycol (PEG) 1000 succinate (TPGS),PEG-40 hydrogenated castor oil (CREMOPHOR RH40), PEG-35 castor oil(CREMOPHOR EL), PEG-40 stearate (MYRJ 540), hard fat (such as GELUCIRE33/01), polyoxylglycerides (such as GELUCIRE 44/14), stearoylpolyoxylglycerides (such as GELUCIRE 50/13), PEG-8 caprylic/capricglycerides (such as LABRASOL) and poloxamers (such as PLURONIC,KOLLIPHOR).

In some embodiments, the pharmaceutical compositions may comprise anilotinib ASD and one or more pharmaceutically acceptable excipients,with the proviso that the pharmaceutically acceptable excipients do notcomprise polyvinyl caprolactam-polyvinyl acetate-polyethylene glycolgraft co-polymer (e.g., SOLUPLUS).

Buffering agents that may be used in the pharmaceutical compositions ofthe present disclosure include, but are not limited to, triethylamine,meglumine, diethanolamine, ammonium acetate, arginine, lysine,histidine, a phosphate buffer (e.g., sodium phosphate tribasic, sodiumphosphate dibasic, sodium phosphate monobasic, or o-phosphoric acid),sodium bicarbonate, a Britton-Robinson buffer, a Tris buffer (containingTris(hydroxymethyl)-aminomethane), a HEPES buffer (containingN-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid), acetate, acitrate buffer (e.g., citric acid, citric acid anhydrous, citratemonobasic, citrate dibasic, citrate tribasic, citrate salt), ascorbate,glycine, glutamate, lactate, malate, formate, sulfate, and mixturesthereof.

Further, pH-adjusting agents that may be used in the pharmaceuticalcompositions of the present disclosure include pharmaceuticallyacceptable acids or bases. For example, acids may include, but are notlimited to, one or more inorganic mineral acids such as hydrochloric,hydrobromic, sulfuric, phosphoric, nitric, and the like; or one or moreorganic acids such as acetic, succinic, tartaric, ascorbic, citric,glutamic, benzoic, methanesulfonic, ethanesulfonic, trifluoroacetic, andthe like. The bases may be one or more inorganic bases or organic bases,including, but not limited to, alkaline carbonate, alkaline bicarbonate,alkaline earth metal carbonate, alkaline hydroxide, alkaline earth metalhydroxide, or amine. For example, the inorganic or organic base may bean alkaline hydroxide such as lithium hydroxide, potassium hydroxide,cesium hydroxide, sodium hydroxide, or the like; an alkaline carbonatesuch as calcium carbonate, sodium carbonate, or the like; or an alkalinebicarbonate such as sodium bicarbonate, or the like; the organic basemay also be sodium acetate.

Surfactants that may be used in the pharmaceutical compositions of thepresent disclosure may include, but are not limited to, sodium laurylsulfate, docusate sodium, dioctyl sodium sulfosuccinate, dioctyl sodiumsulfonate, benzalkonium chloride, benzethonium chloride, lauromacrogol400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil(e.g., polyoxyethylene hydrogenated castor oil 10, 50, or 60), glycerolmonostearate, polysorbate (e.g., polysorbate 40, 60, 65, or 80), sucrosefatty acid ester, methyl cellulose, polyalcohols and ethoxylatedpolyalcohols, thiols (e.g., mercaptans) and derivatives, poloxamers,polyethylene glycol-fatty acid esters (e.g., KOLLIPHOR RH40, KOLLIPHOREL), lecithins, and mixtures thereof.

Antioxidants that may be used in the pharmaceutical compositions of thepresent disclosure include, but are not limited to, acetylcysteine,ascorbyl palmitate, BHA, BHT, monothioglycerol, potassium nitrate,sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite,sodium bisulfate, vitamin E or a derivative thereof, propyl gallate,EDTA (e.g., disodium edetate), DTPA, bismuth sodium triglycollamate, ora combination thereof. Antioxidants may also comprise amino acids suchas methionine, histidine, cysteine and those carrying a charged sidechain, such as arginine, lysine, aspartic acid, and glutamic acid. Anystereoisomer (e.g., l-, d-, or a combination thereof) of any particularamino acid (e.g., methionine, histidine, arginine, lysine, isoleucine,aspartic acid, tryptophan, threonine and combinations thereof) orcombinations of these stereoisomers, may be present so long as the aminoacid is present either in its free base form or its salt form.

Carriers that may be used in the pharmaceutical compositions of thepresent disclosure include, but are not limited to, water, saltsolutions (e.g., Ringer's solution and the like), alcohols, oils,gelatins, and carbohydrates such as lactose, amylose or starch, fattyacid esters, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl pyrrolidine, and mixtures or solutions includingany of the foregoing. The carrier may be used in combination with abuffering agent.

In some embodiments, the composition of the present disclosure maycomprise a carrier at a pH from 5 to 9, or from 6 to 8. In certainembodiments, the composition may comprise a carrier having a neutral pH.In certain embodiments, the pH of the carrier may be at or nearphysiological pH.

In some embodiments, the pharmaceutical compositions of the presentdisclosure may include other suitable pharmaceutical additives suchtonicity-adjusting agents, preservatives, emulsifiers, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers, and osmo-regulators.

Pharmaceutical compositions in solid form may comprise one or morefillers, one or more binders, one or more lubricants, one or moredisintegrants, and/or other conventional excipients such as one or moreglidants, for example.

Suitable fillers include acacia, calcium carbonate, calcium sulfate,calcium sulfate dihydrate, compressible sugar, dibasic calcium phosphateanhydrous (e.g., FUJICALIN, EMCOMPRESS), dibasic calcium phosphatedihydrate, tribasic calcium phosphate, monobasic sodium phosphate,dibasic sodium phosphate, lactose monohydrate, lactose anhydrous,magnesium oxide, magnesium carbonate, silicon dioxide, magnesiumaluminum silicate, maltodextrin, mannitol, methyl cellulose,microcrystalline cellulose (e.g., AVICEL PH-101, AVICEL PH-102),powdered cellulose, starches, sorbitol, dextrose, dextrates, dextrin,sucrose, xylitol and mixtures thereof.

Suitable binders include various celluloses and cross-linkedpolyvinylpyrrolidone, microcrystalline cellulose (e.g., AVICEL PH-101,AVICEL PH-102, AVICEL PH-105), or silicified microcrystalline cellulose(e.g., PROSOLV SMCC), for example.

One or more lubricants may be included to reduce friction with andadherence to processing equipment during processing. Examples ofsuitable lubricants include, but are not limited to, magnesium stearate,calcium stearate, zinc stearate, stearic acid, stearyl alcohol, glycerylmonostearate, sodium stearyl fumarate, talc, glyceryl behenate, sodiumbenzoate, sodium lauryl sulfate, and the like. When included, the one ormore lubricant is generally present in the range of 0.1% to 5%, byweight of the pharmaceutical composition. In some embodiments, the oneor more lubricant is generally present in the range of 0.25% to 2%, byweight of the pharmaceutical composition. In certain embodiments, thelubricant is magnesium stearate.

Suitable disintegrants in the practice of the disclosure includenatural, modified or pre-gelatinized starch, sodium starch glycolate,sodium carboxymethyl cellulose, calcium carboxymethyl cellulose,croscarmellose sodium, crospovidone, polyvinylpolypyrrolidone (“PVPP”),and mixtures thereof.

Glidants are employed to improve flow properties of a powder or granulemixture prior to further processing (such as tablet compression, forexample). Suitable glidants that may be employed in the compositions ofthe present disclosure include, but are not limited to, fumed silica(e.g., CAB-O-SIL), colloidal silica, hydrophobic colloidal silica (e.g.,AEROSIL R972), hydrophilic colloidal silica (e.g., AEROSIL 200 PHARMA),silica gel, precipitated silica, and the like. When included, the one ormore glidant is generally present in the range of 0.1% to 5%, by weightof the pharmaceutical composition. In some embodiments, the one or moreglidant is present in the range of 0.25% to 2%, by weight of thepharmaceutical composition.

In some cases, a single excipient may provide more than one function.For example, microcrystalline cellulose (when present) can function asboth a filler and a binder. Alternatively, such multi-functionalexcipients can be used in combination with other functional excipients.(For example, microcrystalline cellulose may be used with other fillersand/or other binders.)

In some embodiments, the pharmaceutical compositions may be in the formof granules, or may be prepared as granules as an intermediate step toforming another oral dosage form, such as a tablet or pellet, or as afill for a capsule. In some embodiments, the granules may comprise oneof more of the pharmaceutically acceptable excipients described above.In certain embodiments, the granules may comprise the ASD in an amountof 50% to 70% by weight of the granule; one or more fillers in an amountof 20% to 40% by weight of the granule; one or more disintegrants in anamount of 1% to 15% by weight of the granule; and one or more lubricantsin an amount of 0.2% to 5% by weight of the granule. In particularembodiments, the granule may comprise the components as set forth inTable 1.

TABLE 1 Components of an exemplary granule formulation in accordancewith particular embodiments of the disclosure. % By Weight Component ofthe Granule Nilotinib ASD  50-70% Mannitol  20-40% Croscarmellose Sodium  2-10% Colloidal Silica 0.2-5% (optional) Magnesium stearate 0.2-5%(optional)

In some embodiments, the pharmaceutical compositions are in the form ofa tablet. In certain embodiments, the tablet may comprise the ASD in anamount of 20% to 40% by weight of the tablet; one or more fillers (sucha mannitol and/or microcrystalline cellulose) in an amount of 40% to 70%by weight of the tablet; one or more disintegrants (such ascroscarmellose sodium) in an amount of 5% to 15% by weight of thetablet; one or more lubricants and/or glidants (such as hydrophobiccolloidal silica and/or magnesium stearate) in an amount of 0.5% to 5%by weight of the tablet; one or more binders (such as crospovidone) inan amount of 1% to 10% by weight of the tablet.

Pharmaceutical compositions of the disclosure in the form of a tabletmay be prepared using methods known in the art. For example, thenilotinib ASD and the one or more pharmaceutically acceptable additivesmay be blended to provide a tableting blend by hand or bag blending, orusing a suitable device. Examples of suitable blending devices mayinclude, but are not limited to, a tumble blender, v-blender, acousticblender, paddle mixer, screw mixer, and the like.

Suitable tableting blends may then be compressed into tablets having atarget weight from 50 to 1000 mg using, for example, a manual tabletpress or a conventional mechanical tablet press. Compression force isselected to achieve desired mechanical properties of the tablet withoutcompromising performance.

In some embodiments, it may be desirable to form granules as anintermediate step to forming a tableting blend. Granules typically haveimproved flow, handling, blending, and compression properties relativeto ungranulated materials. The granules may be prepared from the ASDparticles by processes known in the art, including wet granulation anddry granulation. In some embodiments, a granulation blend is formed bydry-blending granule components, and then the granulation blend isdensified using a roller compactor which typically forms ribbons ofmaterial. The ribbons are then reduced in size by milling to formgranules.

Wet granulation techniques may also be employed to form granules,provided the solvents and process selected do not alter the propertiesof the ASD. Improved wetting, disintegrating, dispersing and dissolutionproperties may be obtained by the inclusion of suitable excipients, asdescribed above.

The granulation blend (and accordingly the resulting granules) caninclude some or all of the components of the tablet. In someembodiments, the granules may comprise one of more of thepharmaceutically acceptable excipients described above. Aftergranulation, the granules can be included into a tableting blend andcompressed into tablets, as described above.

The pharmaceutical compositions of the present disclosure maydemonstrate a desirable level of physical and/or chemical stability oversome suitable period of time, and optionally under acceleratedconditions. The stability of the pharmaceutical compositions can beassessed by different measures. For instance, the pharmaceuticalcompositions may demonstrate chemical stability by having a particularassay value or a particular level of total related substances (e.g.,impurities), measured after storage under accelerated conditions over aspecified period of time. In some embodiments, the pharmaceuticalcompositions may be amorphous as assessed using XRD (i.e., nocrystalline character detected) after storage under the specifiedconditions.

In some embodiments, the pharmaceutical compositions may besubstantially amorphous as assessed using XRD, after storage under thespecified conditions. The storage conditions may be one or more of 25°C./60% RH, or 30° C./65% RH, or 40° C./75% RH. The period of time may beone or more of 1 week, or 2 weeks, or 1 month, or 2 months, or 3 months,or 4 months, or 6 months, or 9 months, or 12 months, or 15 months, or 18months, or 21 months, or 24 months, or any period of time therebetween.

In some embodiments, pharmaceutical compositions of the presentdisclosure are “gastric acid-insensitive compositions,” as furtherdescribed below. In some embodiments, pharmaceutical compositions of thepresent disclosure are “food-insensitive compositions,” as furtherdescribed below. In some embodiments, pharmaceutical compositions of thepresent disclosure are “improved variability compositions,” as furtherdescribed below.

Orally Disintegrating Tablets

An aspect of the present disclosure relates to pharmaceuticalcompositions comprising an ASD of nilotinib. In particular, in oneaspect the present disclosure provides a pharmaceutical composition inthe form of an orally disintegrating tablet.

Pertaining to orally disintegrating tablets, the U.S. Food and DrugAdministration (“FDA”) has published “Guidance for Industry: OrallyDisintegrating Tablets” (Center for Drug Evaluation and Research (CDER),Food and Drug Administration (FDA), December 2008), which is herebyincorporated by reference in its entirety, and is referred to herein as“ODT Guidance.” Per the ODT Guidance, an orally disintegrating tablet(“ODT”) is “ . . . designed to disintegrate or dissolve rapidly oncontact with saliva, thus eliminating the need to chew the tablet,swallow an intact tablet, or take the tablet with liquids.” Suchproducts are intended to be more convenient to use, and are alsointended to address potential issues of patient compliance for certainpatient populations, including pediatric patients, geriatric patients,and patients with conditions related to impaired swallowing (referred toherein as “dysphagia”).

The European Pharmacopoeia employs a similar term, “orodispersible,” fora tablet that disperses rapidly when placed in the mouth. It should beunderstood that the orally disintegrating tablets of the presentdisclosure also meet the term “orodispersible” under the EuropeanPharmacopoeia definition. For the purposes of this specification, thephrases “orally disintegrating tablet” and “orodispersible tablet”should be considered synonymous.

The orally disintegrating tablet of the disclosure comprises a nilotinibASD and one or more pharmaceutically acceptable excipients, such as oneor more fillers, one or more disintegrants, one or more glidants, and/orother optional excipients that are beneficial for an orallydisintegrating tablet, such as effervescent agents, flavorants,taste-masking agents, sweeteners, and the like. Pharmaceuticalcompositions may further include other conventional excipients such asone or more lubricants, one or more solubilizers, one or moresurfactants, and/or one or more antioxidants, for example.

The orally disintegrating tablet may comprise 10% to 75% of thenilotinib ASD, based on the weight of the tablet. In some embodiments,the orally disintegrating tablet comprises 15% to 60% of the nilotinibASD. In other embodiments, the orally disintegrating tablet comprises20% to 50% of the nilotinib ASD. In other embodiments, the orallydisintegrating tablet comprises 25% to 40% of the nilotinib ASD. In yetother embodiments, the orally disintegrating tablet comprises 30% of thenilotinib ASD.

The proportion of ASD in the tablet will be determined by a number offactors, including the nominal nilotinib dosage to be provided by thetablet, the targeted overall tablet size, and the drug load of nilotinibin the ASD. Suitable orally disintegrating tablets according to thepractice of the disclosure will generally comprise a nominal dosage of10 mg to 100 mg nilotinib. In some embodiments, the orallydisintegrating tablets will comprise a nominal dosage of 15 mg to 75 mgnilotinib. Specific embodiments of the disclosure may nominally comprise10 mg nilotinib, or 15 mg nilotinib, or 20 mg nilotinib, or 25 mgnilotinib, or 30 mg nilotinib, or 35 mg nilotinib, or 40 mg nilotinib,or 45 mg nilotinib, or 50 mg nilotinib, or 55 mg nilotinib, or 60 mgnilotinib, or 65 mg nilotinib, or 70 mg nilotinib, or 75 mg nilotinib,or 80 mg nilotinib, or 85 mg nilotinib, or 90 mg nilotinib, or 95 mgnilotinib, or 100 mg nilotinib.

Fillers. Suitable fillers in the practice of the disclosure includeacacia, calcium carbonate, calcium sulfate, calcium sulfate dihydrate,compressible sugar, dibasic calcium phosphate anhydrous (e.g.,FUJICALIN), dibasic calcium phosphate dihydrate, tribasic calciumphosphate, monobasic sodium phosphate, dibasic sodium phosphate, lactosemonohydrate, lactose anhydrous, magnesium oxide, magnesium carbonate,silicon dioxide, magnesium aluminum silicate, maltodextrin, mannitol,methyl cellulose, microcrystalline cellulose (e.g., AVICEL PH-101,AVICEL PH-102), powdered cellulose, sorbitol, dextrose, dextrates,dextrin, sucrose, xylitol and mixtures thereof. Of these fillers,microcrystalline cellulose, mannitol, and combinations thereof may beparticularly suitable for some embodiments.

Also suitable as fillers are a variety of marketed co-processedexcipients that have found application in pharmaceutical formulations. Aco-processed excipient is any combination of two or more excipientspre-processed by physical co-processing that does not generally lead tothe formation of covalent bonds. Co-processed excipients can possesssuperior properties as compared to individual excipients. Co-processedexcipients been developed primarily to improve flowability,compressibility, and disintegration performance.

By way of example, co-processed excipients comprising microcrystallinecellulose may be suitably employed in some embodiments. Co-processedexcipients comprising sugars or sugar alcohols (such as mannitol andlactose) may also be suitably employed. Such co-processed excipients mayprovide an additional benefit to an orally disintegrating tablet, inthat they may impart a mildly sweet taste to the composition.Co-processed excipients comprising both microcrystalline cellulose and asugar or sugar alcohol may also be suitably employed in someembodiments.

Co-processed excipients comprising microcrystalline cellulose include(as non-limiting examples): co-processed microcrystalline cellulose andmannitol (e.g., AVICEL HFE); co-processed microcrystalline cellulose andcolloidal silica (e.g., PROSOLV SMCC, AVICEL SMCC); co-processedmicrocrystalline cellulose and dibasic calcium phosphate (e.g., AVICELDG); co-processed microcrystalline cellulose and lactose (e.g.,MICROLELA).

Co-processed excipients comprising both microcrystalline cellulose and asugar or sugar alcohol include (as non-limiting examples): co-processedmicrocrystalline cellulose and mannitol (e.g., AVICEL FIFE);co-processed microcrystalline cellulose and lactose (e.g., MICROLELA).

Co-processed excipients comprising sugars or sugar alcohols include (asnon-limiting examples): co-processed lactose and povidone (e.g.,LUDIPRESS); co-processed lactose and cellulose (e.g., CELLACTOSE);co-processed mannitol and starch (e.g., PEARLITOL FLASH); co-processedmannitol, crospovidone and silicon dioxide (e.g., PHARMABURST).

One co-processed excipient that has been identified as particularlysuitable is a co-processed mannitol and starch available under the tradename PEARLITOL FLASH. PEARLITOL FLASH is a co-processed productcomprising approximately 80% d-mannitol and 20% maize starch, and ischaracterized by a particle size distribution having a Dv90 of 300 μm.It is described as a direct-compression excipient with disintegrantproperties, and is stated to provide consistent rapid disintegrationtimes. PEARLITOL FLASH is generally chemically inert and is stated tohave a pleasant taste and texture for use in orally dispersible tablets.PEARLITOL FLASH is commercially available from Roquette.

In some embodiments, co-processed mannitol and starch may beparticularly suitable as a filler, alone or in combination with one ormore other fillers. In particular embodiments, a combination ofco-processed mannitol starch and microcrystalline cellulose may beparticularly suitable.

Generally, the orally disintegrating tablet will comprise from 10% to80% of the one or more fillers, by weight of the tablet. In someembodiments, the orally disintegrating tablet comprises 20% to 75% ofthe one or more fillers. In other embodiments, the orally disintegratingtablet comprises 30% to 70% of the one or more fillers. In yet otherembodiments, the orally disintegrating tablet comprises 40% to 65% ofthe one or more fillers. In yet other embodiments, the orallydisintegrating tablet comprises 50% to 65% of the one or more fillers.In particular embodiments, the tablet comprises 30%, or 35%, or 40%, or45%, or 50%, or 55%, or 60%, or 65%, or 70% of the one or more fillers.

In the foregoing, where a combination of fillers is employed, thecombination can comprise a balanced ratio of the fillers, or anunbalanced ratio of the fillers. For two fillers, for example, the twofillers can be present in a 1:1 ratio (by weight) of the two fillers, oran unbalanced ratio such as 1:2, 1:3, 1:4, or 1:5, for example. A 1:1ratio has been suitably employed in particular embodiments.

Disintegrants. One or more disintegrants are generally included in theorally disintegrating tablet to quickly wick saliva into the tabletwhich causes rapid disintegration in the mouth. Suitable disintegrantsin the practice of the disclosure include natural, modified orpre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, croscarmellose sodium,crospovidone, polyvinylpolypyrrolidone (“PVPP”), and mixtures thereof.Of these, crospovidone, croscarmellose sodium, and combinations thereofmay be particularly suitable.

Generally, the orally disintegrating tablet will comprise from 2% to 20%of the one or more disintegrants, by weight of the tablet. In otherembodiments, the orally disintegrating tablet will comprise from 5% to15% of the one or more disintegrants. In certain embodiments, the orallydisintegrating tablet will comprise from 5% to 10% of the one or moredisintegrants. In other embodiments, the orally disintegrating tabletwill comprise from 8% to 12% of the one or more disintegrants. Inparticular embodiments, the orally disintegrating tablet will comprise2%, or 3%, or 4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 11%, or12%, or 13%, or 14%, or 15%, or 16%, or 17%, or 18%, or 19%, or 20% ofthe one or more disintegrants.

In the foregoing, where a combination of disintegrants is employed, thecombination can comprise a balanced ratio of the disintegrants, or anunbalanced ratio of the disintegrants. For two disintegrants, forexample, the two disintegrants can be present in a 1:1 ratio (by weight)of the two disintegrants, or an unbalanced ratio such as 1:2, 1:3, 1:4,or 1:5, for example.

In certain embodiments, the orally disintegrating tablet comprises from2% to 20% of a combination of crospovidone and croscarmellose sodium, byweight of the tablet, as disintegrants. In other embodiments, the orallydisintegrating tablet will comprise from 5% to 15% of a combination ofcrospovidone and croscarmellose sodium. In other embodiments, the orallydisintegrating tablet will comprise from 8% to 12% of a combination ofcrospovidone and croscarmellose sodium. In certain embodiments, theorally disintegrating tablet will comprise 12% of a combination ofcrospovidone and croscarmellose sodium. In the foregoing, thecombination of crospovidone and croscarmellose sodium can comprise a 1:1ratio (by weight) of crospovidone and croscarmellose sodium, or anunbalanced ratio such as 1:2, 1:3, 1:4, or 1:5, or 2:1, 3:1, 4:1, or5:1, for example. A 1:1 ratio has been suitably employed in particularembodiments.

In other embodiments, the orally disintegrating tablet comprises aco-processed excipient as filler (alone or in combination with one ormore other fillers) as described above, along with one or moredisintegrants. Where the co-processed excipient provides somedisintegrant properties, a lower portion of the one or moredisintegrants may be suitably employed. In certain embodiments, theorally disintegrating tablet comprises a co-processed excipient as afiller in a quantity as specified above, along with 3% to 15% of the oneor more disintegrants, or 5% to 10% of the one or more disintegrants. Inthese embodiments, the orally disintegrating tablet may comprise 3%, or4%, or 5%, or 6%, or 7%, or 8%, or 9%, or 10%, or 11%, or 12%, or 13%,or 14%, or 15% of the one or more disintegrants. In some embodiments,the co-processed excipient is co-processed mannitol starch.

In particular embodiments, the orally disintegrating tablet comprisesco-processed mannitol starch as a filler (alone or in combination withone or more other fillers) as described above, along with crospovidoneas a disintegrant. By way of example, a suitable embodiment employs acombination of microcrystalline cellulose and co-processed mannitolstarch in a 1:1 ratio as fillers, and crospovidone as disintegrant. Inone such embodiment, the orally disintegrating tablet comprises 40% to65% of microcrystalline cellulose and co-processed mannitol starch in a1:1 ratio as fillers, and 5% to 10% crospovidone as disintegrant.

Glidants. Glidants may be employed to improve flow properties of apowder or granule mixture prior to tablet compression. Suitable glidantsthat may be employed in the compositions of the present disclosureinclude, but are not limited to, fumed silica (e.g., CAB-O-SIL),colloidal silica, hydrophobic colloidal silica (e.g., AEROSIL R972),hydrophilic colloidal silica (e.g., AEROSIL 200 PHARMA), silica gel,precipitated silica, and the like. One or more glidants can optionallybe included in the orally disintegrating tablet. When included, the oneor more glidant is generally present in the range of 0.1% to 5%, byweight of the tablet.

In some embodiments, the one or more glidant is present in the range of0.25% to 2%, by weight of the orally disintegrating tablet. In certainembodiments, the glidant comprises hydrophobic colloidal silica. Incertain other embodiments, the glidant is hydrophobic colloidal silica.In yet other embodiments, the glidant comprises hydrophilic colloidalsilica. In yet other embodiments, the glidant is hydrophilic colloidalsilica. In other embodiments, the glidant can be a combination ofsuitable excipients, such as a combination of hydrophobic colloidalsilica and hydrophilic colloidal silica.

Other components. A variety of other components may suitably be employedin the orally disintegrating tablet. For example, the orallydisintegrating tablet may include effervescent agents, flavorants,taste-masking agents, sweeteners, and the like. The inclusion of thesecomponents, and the suitable quantities, is within the purview of oneskilled in the art.

In some embodiments, effervescent systems can optionally be employed toaid in disintegration of the orally disintegrating tablet. Effervescentsystems are known in the art. Effervescent systems generally include aseffervescent agents both a soluble organic acid and an alkali metalcarbonate salt. When the tablet is wetted by saliva, carbon dioxide isformed from the reaction of the acid and carbonate salt, and theeffervescent action contributes to the rapid disintegration of thetablet. Examples of suitable acids include citric acid, tartaric acid,malic acid, fumaric acid, adipic acid, and combinations thereof.Examples of suitable carbonate salts include sodium bicarbonate, sodiumcarbonate, sodium sesquicarbonate, potassium bicarbonate, potassiumcarbonate, and combinations thereof. In other embodiments, the orallydisintegrating tablet does not include effervescent agents.

Flavorants may optionally be included in the orally disintegratingtablet. Suitable flavorants include natural or synthetic mint, orange,lemon, peppermint, vanilla, bubble gum, strawberry, cherry, caramel,raspberry, banana, and the like, or appropriate combinations thereof. Insome embodiments, one or more flavorants may be present in aconcentration of 0.1-1.0% by weight. In other embodiments, the orallydisintegrating tablet is free from flavorants.

Taste-masking agents can optionally be included. Certain agents likementhol provide a cool sensation and numb the taste buds to retard theperception of bitter taste. Other agents such as bitterness inhibitorscan also be added. Suitable taste-masking agents are known in the art.In some embodiments of the disclosure, the orally disintegrating tabletis free from taste-masking agents.

A suitable natural or artificial sweetener may optionally be included inthe orally disintegrating tablet. In some embodiments, a selected fillermay be a sugar, carbohydrate, or derivative thereof, and may impart somesweetness without the inclusion of an additional sweetener. By way ofexample, mannitol or co-processed mannitol starch may provide sweetnessin addition to acting as a filler. In other embodiments, a sweetener (orcombination of sweeteners) may be included. Suitable natural andartificial sweeteners are known in the art. Exemplary sweeteners includesugars and sugar derivatives (such as sucrose, dextrose, fructose, andlactose, for example), aspartame, acesulfame potassium, sucralose,sodium cyclamate, saccharin, sorbitol, xylitol, mannitol, and the like.Establishing the quantity of sweetener to include is within the abilityof those skilled in the art. Broadly speaking, however, artificialsweeteners are generally quite potent and can be used in very smallquantities.

One or more lubricants may be included to reduce friction with andadherence to processing equipment during processing and tableting.Examples of suitable lubricants include, but are not limited to,magnesium stearate, calcium stearate, zinc stearate, stearic acid,stearyl alcohol, glyceryl monostearate, sodium stearyl fumarate, talc,glyceryl behenate, sodium benzoate, sodium lauryl sulfate, and the like.One or more lubricants can optionally be included in the orallydisintegrating tablet. When included, the one or more lubricant isgenerally present in the range of 0.1% to 5%, by weight of the tablet.In some embodiments, the one or more lubricant is generally present inthe range of 0.25% to 2%, by weight of the tablet. In certainembodiments, the lubricant is magnesium stearate.

Solubilizers, surfactants, and/or antioxidants may further be included,as appropriate. Suitable solubilizers and surfactants are describedabove. The inclusion of these components, and the suitable quantities,is within the purview of one skilled in the art.

Antioxidants that may be optionally included in the pharmaceuticalcompositions of the present disclosure include, but are not limited to,acetylcysteine, ascorbyl palmitate, BHA, BHT, monothioglycerol,potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate,sodium metabisulfite, sodium bisulfite, vitamin E or a derivativethereof, propyl gallate, EDTA (e.g., disodium edetate), DTPA, bismuthsodium triglycollamate, or a combination thereof. When included, the oneor more antioxidant is generally present in the range of 0.05% to 2%, byweight of the tablet. In some embodiments, the one or more antioxidantis generally present in the range of 0.05% to 0.5%, by weight of thetablet. In certain embodiments, the antioxidant is BHT.

Manufacture of Orally Disintegrating Tablets

The orally disintegrating tablets of the present disclosure may beprepared using methods known in the art. For example, the nilotinib ASDand the one or more pharmaceutically acceptable additives may be blendedto provide a tableting blend by hand or bag blending, or using asuitable device. Examples of suitable blending devices may include, butare not limited to, a tumble blender, v-blender, acoustic blender,paddle mixer, screw mixer, and the like. In preparing blend compositionsfor tableting, it has been found that optionally employing anintensifier bar (“I-bar”) in a mechanical blending apparatus has beenbeneficial for ensuring thorough blending and to reduce agglomeration.

Suitable tableting blends may then be compressed into tablets weighingfrom 50 to 1000 mg using, for example, a manual tablet press or aconventional mechanical tablet press. In the case of orallydisintegrating tablets, compression force must be carefully selected toachieve desired mechanical properties of the tablet without compromisingperformance. If too high a compression force is used, the porosity ofthe tablet decreases, which can slow the rate of water wicking into thetablet, and can undesirably result in increased disintegration timesand/or degraded dissolution performance.

For some embodiments, a tableting blend may be prepared and directlycompressed into tablets (otherwise known as direct compression).

In other embodiments, it may be desirable to form granules as anintermediate step to forming the tableting blend. Granules typicallyhave improved flow, handling, blending, and compression propertiesrelative to ungranulated materials. The granules may be prepared fromthe ASD particles by processes known in the art, including wetgranulation and dry granulation.

In some embodiments, a granulation blend is formed by dry-blendinggranule components (as described above), and then the granulation blendis densified using a roller compactor which typically forms ribbons ofmaterial. The ribbons are then reduced in size by milling to formgranules. Wet granulation techniques may also be employed to formgranules, provided the solvents and process selected do notsignificantly alter the properties of the solid amorphous dispersion.

The granulation blend (and accordingly the resulting granules) caninclude some or all of the components of the orally disintegratingtablet. Improved wetting, disintegrating, dispersing and dissolutionproperties may be obtained by the inclusion of suitable excipients, asdescribed above. Generally, the granules comprise the ASD and one ormore of the pharmaceutically acceptable excipients described above. Inthis context, such excipients are referred to as “intra-granular.”

In certain embodiments, the granulation blend may comprise the ASD in anamount of 20% to 80%, or in an amount of 25% to 75%, by weight. Inparticular embodiments, the granulation blend comprises 20%, or 25%, or30%, or 35%, or 40%, or 45%, or 50%, or 55%, or 60%, or 65%, or 70%, or75%, or 80% of the ASD, by weight. When a higher proportion ofextra-granular excipients is employed, then the granulation blendaccordingly would contain a relatively high proportion of the ASD; if alower proportion of extra-granular excipients is employed, then thegranulation blend can contain a relatively lower proportion of the ASD.

In certain embodiments, the granules may comprise the ASD in an amountof 20% to 80%, more suitably 25% to 75% by weight of the granule; one ormore granulation fillers in an amount of 15% to 60%, more suitably 20%to 40% by weight of the granule; one or more granulation disintegrantsin an amount of 2% to 20%, more suitably 5% to 15% by weight of thegranule; and optionally one or more lubricants in an amount of 0.2% to5% by weight of the granule; and optionally one or more glidants in anamount of 0.2% to 5% by weight of the granule. Such a granule may besuitable when a relatively higher proportion of extra-granularexcipients is employed. In a particular embodiment, the granule maycomprise the components as set forth in Table 1A.

TABLE 1A Components of an exemplary granule formulation in accordancewith particular embodiments. % By Weight Component of the GranuleNilotinib ASD  50-70% Mannitol  20-40% Croscarmellose Sodium   5-15%Colloidal Silica 0.2-5% (optional) Magnesium stearate 0.2-5% (optional)

In certain other embodiments, the granules may comprise the ASD in anamount of 20% to 60%, more suitably 25% to 50% by weight of the granule;one or more granulation fillers in an amount of 40% to 80%, moresuitably 50% to 70% by weight of the granule; one or more granulationdisintegrants in an amount of 2% to 10%, more suitably 4% to 8% byweight of the granule; and optionally one or more lubricants in anamount of 0.2% to 5% by weight of the granule; and optionally one ormore glidants in an amount of 0.2% to 5% by weight of the granule. Sucha granule may be suitable when a relatively lower proportion ofextra-granular excipients is employed. In particular embodiments, thegranule may comprise the components as set forth in Table 1B, whichincludes one or a combination of fillers.

TABLE 1B Components of an exemplary granule formulation in accordancewith particular embodiments. % By Weight Component of the GranuleNilotinib ASD  25-40% Co-processed Mannitol Starch   0-60%Microcrystalline Cellulose   0-60% Crospovidone   2-10% Colloidal Silica0.2-5% (optional) Magnesium stearate 0.2-5% (optional)

In other embodiments, the granule may comprise the components as setforth in Table 1C, which utilizes a combination of fillers.

TABLE 1C Components of an exemplary granule formulation in accordancewith particular embodiments. % By Weight Component of the GranuleNilotinib ASD  25-40% Co-processed Mannitol Starch  20-40%Microcrystalline Cellulose  20-40% Crospovidone   2-10% Colloidal Silica0.2-5% (optional) Magnesium stearate 0.2-5% (optional)

In some embodiments, the orally disintegrating tablets of the disclosureinclude granules as described above, along with additional excipientsexternal to the granules (“extra-granular excipients”). Accordingly, asuitable tableting blend would comprise granules and the extra-granularexcipients.

In one embodiment, the orally disintegrating tablet comprises from 20%to 80% of the granules, by weight of the tablet; and 20% to 80% of theextra-granular excipients, by weight of the tablet. In certainembodiments, the orally disintegrating tablet comprises from 30% to 70%of the granules, by weight of the tablet; and 30% to 70% of theextra-granular excipients, by weight of the tablet. In yet otherembodiments, the orally disintegrating tablet comprises from 40% to 60%of the granules, by weight of the tablet; and 40% to 60% of theextra-granular excipients, by weight of the tablet. In one particularembodiment, the orally disintegrating tablet comprises 50% of thegranules, and 50% of the extra-granular excipients, by weight of thetablet.

In other embodiments, the orally disintegrating tablet comprises from80% to 99.5% of the granules, by weight of the tablet; and 0.5% to 20%of the extra-granular excipients, by weight of the tablet. In certainembodiments, the orally disintegrating tablet comprises from 95% to99.5% of the granules, by weight of the tablet; and 0.5% to 5% of theextra-granular excipients, by weight of the tablet.

By way of example, the extra-granular excipients could include one ormore tablet fillers and/or one or more tablet disintegrants. Suitablefillers and disintegrants are described above. In some embodiments, theone or more tablet fillers comprises mannitol. In some embodiments, theone or more tablet fillers comprise a combination of mannitol andmicrocrystalline cellulose.

In some embodiments, the one or more tablet disintegrants includes acombination of disintegrants. In some embodiments, the one or moretablet disintegrants includes a combination of crospovidone andcroscarmellose sodium. In one particular embodiment, the one or moretablet disintegrants comprise equal parts by weight of crospovidone andcroscarmellose sodium.

In some embodiments, the one or more tablet disintegrants comprisescrospovidone. In other embodiments, the one or more tablet disintegrantsconsists essentially of crospovidone. In yet other embodiments, the oneor more tablet disintegrants consists of crospovidone.

In some embodiments, the orally disintegrating tablet comprises bothintra-granular disintegrant (referred to as “granulation disintegrant”)and extra-granular disintegrant (referred to as “tablet disintegrant”).In such embodiments, the granulation disintegrant and tabletdisintegrant may be the same, or they may be different. By way ofexample, a suitable orally disintegrating tablet formulation mightinclude crospovidone as a granulation disintegrant and as a tabletdisintegrant.

In addition, the extra-granular excipients could include one or morelubricants and/or one or more glidants. Suitable lubricants and glidantsare described above. Other extra-granular excipients, such assurfactants, solubilizers, and/or antioxidants, could also be employed.

In other embodiments, it may be possible to prepare granules asdescribed above, and then compress the granules directly into tabletswithout additional extra-granular excipients. The tableting blend inthat case consists of granules. In some embodiments, the orallydisintegrating tablet consists essentially of the granules. In otherembodiments, the orally disintegrating tablet consists of the granules.

To achieve optimum patient compliance, orally disintegrating tabletsmust provide a palatable experience to the patient. Upon oraldisintegration, the presence of large particles can result in a grittyfeeling in the mouth. Thus, small particles are preferred. Additionally,if the tablet forms a gel-like consistency on contact with water, itproduces a gummy texture that many consumers find objectionable.Therefore, when using granules to form a tableting blend for themanufacture of orally disintegrating tablets, the size of the granulesshould be controlled to avoid undesirable outcomes.

In practice, a vast majority (at least 90%, more suitably 95% or more,by weight) of the granules should be small enough to pass through a20-mesh sieve. In some embodiments, at least 50% of the granules, byweight, are small enough to pass through a 40-mesh sieve. In someembodiments, not more than 20%, or more suitably not more than 15%, ormost suitably not more than 10% by weight of the granules are largerthan 30 mesh (i.e., would be retained when screened with a 30-meshsieve).

For a pharmaceutical composition in the form of an orally disintegratingtablet, it is generally necessary to protect the dosage units fromexternal moisture. Accordingly, the disclosure provides an orallydisintegrating tablet as described above, stored within packagingmaterial adapted to protect the orally disintegrating tablet fromexternal moisture. In some embodiments, the packaging material includesan individually sealed pouch, such as a metal foil pouch or a pouchformed from a suitable film or laminated material (such as MYLAR). Inother embodiments, the orally disintegrating tablet is individuallysealed in a blister pack. In yet other embodiments, the packagingmaterial is a bottle that includes a desiccant.

Characterization of Orally Disintegrating Tablets

Orally disintegrating tablets are typically characterized by severaldifferent parameters, including disintegration time, tablet friability,tablet breaking force, and in vitro dissolution testing.

The ODT Guidance specifies that an ODT is considered to be a solid oralpreparation “ . . . that disintegrate[s] rapidly in the oral cavity,with an in-vitro disintegration time of approximately 30 seconds orless, when based on the United States Pharmacopeia (USP) disintegrationtest method or alternative . . . .” The relevant USP test method isfully described in USP <701> Disintegration. USP <701> specifies theappropriate basket-rack apparatus, the disks, other experimentaldetails, and the testing procedure. Typically, 6 dosage units aretested. USP <701> indicates that “disintegration” does not implycomplete solution of the dosage unit or of its active constituent withinthe specified time, but that any residue of the dosage unit is a softmass having no palpably firm core.

Accordingly, in one embodiment, the disclosure provides a pharmaceuticalcomposition in the form of an orally disintegrating tablet,characterized by a disintegration time of 40 seconds or less, asdetermined according to USP <701> Disintegration, using a basket-rackapparatus with disks in a medium of distilled water. In otherembodiments, the disintegration time is 35 seconds or less. In otherembodiments, the disintegration time is 30 seconds or less. In otherembodiments, the disintegration time is 25 seconds or less. In yet otherembodiments, the disintegration time is 20 seconds or less. In stillother embodiments, the disintegration time is 15 seconds or less.

Mechanical integrity of tablets when subjected to mechanical stress isassessed by a variety of different tests, including tablet friabilityand tablet breaking force. Friability testing assesses the resistance ofthe dosage unit to chipping and surface abrasion when subjected totumbling in a rotating test drum. Breaking force testing measures theforce required to produce failure (i.e., breakage) in a specified plane,when the dosage unit is subjected to an applied compression forcebetween two platens.

Apparatus and testing procedures for tablet friability testing are fullydescribed in USP <1216> Tablet Friability. The test is generally run ona number of tablets totaling at least 6.5 g, but not fewer than 10tablets. Results are reported as a maximum mean weight loss. Acceptablemean weight loss is somewhat higher for orally disintegrating tabletsthan for tablets meant to be swallowed whole.

Accordingly, in one embodiment, the disclosure provides a pharmaceuticalcomposition in the form of an orally disintegrating tablet,characterized by a maximum mean weight loss of not more than 1.5%, asdetermined according to USP <1216> Tablet Friability. In otherembodiments, the orally disintegrating tablet is characterized by amaximum mean weight loss of not more than 1.0%. In other embodiments,the orally disintegrating tablet is characterized by a maximum meanweight loss of not more than 0.75%. In other embodiments, the orallydisintegrating tablet is characterized by a maximum mean weight loss ofnot more than 0.5%.

Apparatus and testing procedures for tablet breaking force testing arefully described in USP <1217> Tablet Breaking Force. Breaking force istypically reported in kiloponds (“kp”), where 1 kp=9.8 N. Typically asmaller tablet (50-400 mg target tablet weight) may be characterized bya relatively lower breaking force, and larger tablets (400-1000 mgtarget tablet weight) may be characterized by a relatively higherbreaking force.

In some embodiments, the disclosure provides a pharmaceuticalcomposition in the form of an orally disintegrating tablet,characterized by a breaking force of 1 kp to 18 kp, when determinedaccording to USP <1217> Tablet Breaking Force. In other embodiments, thedisclosure provides a pharmaceutical composition in the form of anorally disintegrating tablet, characterized by a breaking force of 2 kpto 12 kp, when determined according to USP <1217> Tablet Breaking Force.In some embodiments, the disclosure provides a pharmaceuticalcomposition in the form of an orally disintegrating tablet,characterized by a breaking force of 2 kp to 8 kp, when determinedaccording to USP <1217> Tablet Breaking Force.

In other embodiments, the disclosure provides a pharmaceuticalcomposition in the form of an orally disintegrating tablet,characterized by a breaking force of 4 kp to 14 kp, when determinedaccording to USP <1217> Tablet Breaking Force. In some embodiments, thedisclosure provides a pharmaceutical composition in the form of anorally disintegrating tablet, characterized by a breaking force of 5 kpto 12 kp, when determined according to USP <1217> Tablet Breaking Force.In some embodiments, the disclosure provides a pharmaceuticalcomposition in the form of an orally disintegrating tablet,characterized by a breaking force of 6 kp to 10 kp, when determinedaccording to USP <1217> Tablet Breaking Force.

In vitro dissolution testing is routinely performed both for qualitycontrol and as a surrogate for in vivo drug release to ensure properexposure for the patient or subject in use. Apparatus and testingprocedures for dissolution testing are fully described in USP <711>Dissolution. For nilotinib hydrochloride monohydrate immediate-releasecapsules, FDA's published recommendations for dissolution testingspecify Apparatus 1 (basket; 100 rpm) using 1000 mL of 0.1 Nhydrochloric acid medium (˜pH 1), with sampling at 10 min, 15 min, 30min and 45 min.

However, for the purposes of assessing the compositions of the presentdisclosure, it has been determined that Apparatus 2 (Paddle Apparatus;100 rpm) using either a maleate buffer (20 mM; pH 3) or citrate buffer(20 mM; pH 3.1) as dissolution medium provides more relevant dissolutioninformation. Dissolution testing under these conditions indicates thatthe orally disintegrating tablets provided by the present disclosure arecapable of delivering nilotinib under conditions mimicking elevatedgastric pH conditions.

In one embodiment, the present disclosure provides an orallydisintegrating tablet characterized in that, when subjected todissolution testing according to USP <711> Dissolution using Apparatus 2at 100 rpm and a dissolution medium consisting of 20 mM maleate bufferat pH 3, at least 10% of the nilotinib is released into the dissolutionmedium within 30 minutes.

In another embodiment, the present disclosure provides an orallydisintegrating tablet characterized in that, when subjected todissolution testing according to USP <711> Dissolution using Apparatus 2at 100 rpm and a dissolution medium consisting of 20 mM citrate bufferat pH 3.1, at least 10% of the nilotinib is released into thedissolution medium within 30 minutes.

In other embodiments of the preceding two paragraphs, at least 20% ofthe nilotinib is released into the dissolution medium within 30 minutes.In another embodiment, at least 25% of the nilotinib is released intothe dissolution medium within 30 minutes. In another embodiment, atleast 30% of the nilotinib is released into the dissolution mediumwithin 30 minutes. In another embodiment, at least 35% of the nilotinibis released into the dissolution medium within 30 minutes. In anotherembodiment, at least 40% of the nilotinib is released into thedissolution medium within 30 minutes. In another embodiment, at least45% of the nilotinib is released into the dissolution medium within 30minutes. In another embodiment, at least 50% of the nilotinib isreleased into the dissolution medium within 30 minutes. In anotherembodiment, at least 55% of the nilotinib is released into thedissolution medium within 30 minutes. In another embodiment, at least60% of the nilotinib is released into the dissolution medium within 30minutes.

Treatment of Proliferative Disorders

Aspects of the present disclosure relate to uses of the nilotinib ASDsof the present disclosure, or pharmaceutical compositions comprising theASDs. In the practice of such embodiments of the present disclosure, thenilotinib ASDs or pharmaceutical compositions may be suitablyadministered to subjects or to patients.

In some embodiments, the nilotinib ASD or pharmaceutical composition isadministered to a subject. The subject in the methods of the presentdisclosure may be a mammal, which includes, but is not limited to, ahuman, monkey, cow, hog, sheep, horse, dog, cat, rabbit, rat, and mouse.In certain embodiments, the subject is a human. As used herein, thephrase “healthy human subject” means a human that is generally healthyand is not being treated for the disease or condition for which thepharmaceutically active component (e.g., nilotinib) is generally usedfor therapy. Selection of suitable healthy human subjects forpharmacokinetic assessment is within the expertise of one skilled in theart of clinical trial design.

In other embodiments, the pharmaceutical composition is administered toa human patient. As used herein, a “patient” is a subject, particularlya human, who is being treated for a disease or condition for which thepharmaceutically active component (e.g., nilotinib) is generally usedfor therapy. The human patient may be adult or of a pediatric age, e.g.,younger than 17 years old. In certain embodiments, the human patient is1 year of age or older.

An aspect of the present disclosure relates to the use of the nilotinibASDs of the present disclosure or pharmaceutical compositions of thepresent disclosure to treat a proliferative disorder. Some embodimentsrelate to a method of treating a proliferative disorder, the methodcomprising administering a nilotinib ASD of the present disclosure, or apharmaceutical composition of the present disclosure, to a patient inneed thereof. Some embodiments relate to a use of a nilotinib ASD or apharmaceutical composition of the present disclosure for treating aproliferative disorder in a patient in need thereof, the use comprisingadministering the nilotinib ASD or pharmaceutical composition to thepatient. Some embodiments relate to a nilotinib ASD or a pharmaceuticalcomposition of the present disclosure for use in treating aproliferative disorder in a patient in need thereof, the use comprisingadministering the nilotinib ASD or the pharmaceutical composition to thepatient. Some embodiments relate to a use of a nilotinib ASD orpharmaceutical composition of the present disclosure in the manufactureof a medicament for treating a proliferative disorder.

In one aspect, the present disclosure relates to a method of treating aproliferative disorder in a patient in need thereof, the methodcomprising administering a therapeutically effective amount of an ASD ofthe present disclosure or of a pharmaceutical composition of the presentdisclosure to the patient.

The proliferative disorder may be cancer. Examples of such proliferativedisorders may include, but are not limited to, leukemias such as acutelymphocytic leukemia (or acute lymphoblastic leukemia), acute myeloidleukemia (or acute myelogenous leukemia), chronic lymphocytic leukemia(or chronic lymphoblastic leukemia), chronic myeloid leukemia (orchronic myelogenous leukemia); age-related macular degeneration anddiabetic retinopathy, anal and oral cancers, angiosarcoma, basal cellcarcinoma and squamous cell carcinoma, bladder cancer, brain cancer,glioma, breast cancer, cancer of the central nervous system, cervical,cervix uteri cancer, choriocarcinoma, colon cancer, gastrointestinalstromal tumor, corpus uteri cancer, esophageal cancer, Ewing's Sarcoma,eye or ocular cancer, head and neck cancer, hemangioendothelioma,hemangiomas and lymphangiogenesis, Kaposi's Sarcoma, larynx cancer,liver cancer, lung cancer, lymphoma, mouth/pharynx cancer, multiplemyeloma; cardiac hypertrophy, neuroblastoma, neurofibromatosis, ovarycancer, pancreatic cancer, prostate cancer, rectal cancer, renal cancer,rhabdomyosarcoma, skin melanoma, small cell lung cancer, stomach cancer,testis cancer, throat cancer, tuberous sclerosis, and Wilms Tumor.

In certain embodiments, the proliferative disorder may be Philadelphiachromosome-positive (“Ph+”) chronic myeloid leukemia (“CML”) in chronicphase. In certain embodiments, the proliferative disorder may be Ph+ CMLin accelerated phase. In certain embodiments, the proliferative disordermay be Ph+ CML with resistance or intolerance to prior tyrosine-kinaseinhibitor therapy. In certain embodiments, the proliferative disordermay be chronic phase or accelerated phase Ph+ CML with resistance orintolerance to prior therapy that included imatinib.

Nilotinib has further been investigated for use in treating Parkinson'sDisease, Huntington's Disease, Alzheimer's Disease, dementia with Lewybodies, cerebellar ataxia, and other non-proliferative disorders. Thecompositions, regimens, kits and other embodiments disclosed hereincould suitably be employed in the treatment of such non-proliferativeconditions.

In the methods and uses of the present disclosure, a therapeuticallyeffective amount of the pharmaceutical composition of the presentdisclosure will be based on, among other factors, the route ofadministration, the age and size of the patient, and the proliferativedisorder being treated. As used herein, the term “therapeuticallyeffective amount” means that amount that is expected to elicit thebiological or medical response that is being sought by a clinician.

In some embodiments, a therapeutically effective amount may be from 50mg/m² to 250 mg/m² of nilotinib, or from 50 mg/m² to 150 mg/m² ofnilotinib, or from 60 to 120 mg/m² of nilotinib. In other embodiments, atherapeutically effective amount may be fixed dose. For instance, thefixed dose may be 20 mg to 400 mg, or 30 mg to 300 mg, or 40 mg to 200mg, per day of nilotinib. In certain embodiments, the fixed dose may be20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, or 55 mg, or 60 mg, or65 mg, or 70 mg, or 75 mg, or 80 mg, or 85 mg, or 90 mg, or 95 mg or 100mg, or 110 mg, or 120 mg, or 125 mg, or 130 mg, or 140 mg, or 150 mg, or160 mg, or 170 mg, or 175 mg, or 180 mg, or 190 mg, or 200 mg, or 210mg, or 220 mg, or 225 mg, or 230 mg, or 240 mg, or 250 mg, or 260 mg, or270 mg, or 275 mg, or 280 mg, or 290 mg, or 300 mg, of nilotinib.

Depending on the treatment regimen, the quantity of nilotinib dosed perday may be dosed twice-per-day, or may be dosed all at once (once-dailydosing), based on labeling guidelines or physician's recommendation. Insome embodiments, dosing is twice daily at approximately 12-hourintervals.

As described further below, pharmaceutical compositions of the presentdisclosure may provide enhanced or otherwise desirable bioavailabilityunder a variety of administration conditions. The term “bioavailability”refers to the rate and extent to which an active ingredient is absorbedfrom a pharmaceutical composition and becomes available at the site ofaction. In the case of orally administered pharmaceuticals,bioavailability is generally assessed by monitoring a subject's bloodplasma over time for the presence of an active ingredient (or suitablesurrogate, such as a metabolite) after administration of apharmaceutical composition, to evaluate the pharmacokinetic profile.

From the pharmacokinetic profile, certain relevant pharmacokineticparameters can be established. Such pharmacokinetic parameters caninclude C_(max), T_(max), and/or AUC, for example. C_(max) indicates themaximum observed plasma concentration over the observed time period.T_(max) indicates the time point at which the maximum plasmaconcentration is observed.

AUC indicates the numerical area-under-the-curve (“AUC”) for theconcentration-time curve, and can be assessed for a specified timeinterval 0-t, denoted as AUC_(0-t) (alternatively denoted as AUC_(t)).AUC_(0-t) is generally obtained by numerical integration of theconcentration-time curve over the period t=0 to the time “t” (e.g.,AUC_(0-24 h) or AUC_(24 h) indicates the integral over the time periodfrom t=0 to t=24 hours). AUC_(0-last) (alternatively denoted asAUC_(last)) indicates the integral from t=0 to the last time pointsampled in the observed time period. AUC_(0-inf) (alternatively denotedas AUC_(inf)) indicates the integral from t=0 to t=“infinity,” which isdetermined by extrapolation of obtained data using commonly employedpharmacokinetic statistical modeling techniques.

Typically, plasma concentration data is log-transformed for analysis.For most pharmacokinetic analyses, data for a number of test subjects ispooled for analysis. When data is pooled, the relevant pharmacokineticparameters may be expressed as a population geometric mean, inaccordance with conventional pharmacokinetic statistical analyses andmethods.

Administration of an ASD or pharmaceutical composition of the presentdisclosure can be characterized by the pharmacokinetic profile, or bythe observed or calculated pharmacokinetic parameters resulting from theadministration of the ASD or pharmaceutical composition at certaindosages to a subject or patient, under stated administration conditions.By way of example only (and as further described below), administrationof the ASD or pharmaceutical composition of the present disclosure undera fasted state or fasting conditions can be characterized by thepharmacokinetic profile resulting from the administration, or byobserved pharmacokinetic parameters.

Methods of Administering with Food

An aspect of the present disclosure relates to a method of treating aproliferative disorder in a patient in need thereof, the methodcomprising administering a therapeutically effective amount of apharmaceutical composition of the present disclosure to the patientwithout a food effect.

In another aspect, the present disclosure relates to a method oftreating a proliferative disorder in a patient in need thereof, themethod comprising administering a therapeutically effective amount of apharmaceutical composition of the present disclosure to the patientwithout regard to consumption of food.

In another aspect, the present disclosure relates to a method oftreating a proliferative disorder in a patient in need thereof, themethod comprising administering a therapeutically effective amount of apharmaceutical composition of the present disclosure to the patientwithout regard to whether the patient is in a fasted state or in a fedstate.

In yet another aspect, the present disclosure relates to a method ofsafely delivering nilotinib to a patient in need thereof, comprisingstep (a), administering a therapeutically effective amount of apharmaceutical composition of the present disclosure to the patient; andstep (b), administering a meal to the patient. In some embodiments, step(b) occurs before step (a). In other embodiments, step (a) occurs beforestep (b). In some embodiments, steps (a) and (b) occur within less thantwo hours of each other. In some embodiments, steps (a) and (b) occurwithin 90 minutes of each other. In some embodiments, steps (a) and (b)occur within one hour of each other. In some embodiments, steps (a) and(b) occur within thirty minutes of each other. In some embodiments,steps (a) and (b) occur within fifteen minutes of each other.

In some embodiments, step (b) occurs less than one hour after step (a).In some embodiments, step (b) occurs less than 30 minutes after step(a). In some embodiments, step (b) occurs less than 15 minutes afterstep (a).

In some embodiments, step (a) occurs less than two hours after step (b).In some embodiments, step (a) occurs less than 90 minutes after step(b). In some embodiments, step (a) occurs less than one hour after step(b). In some embodiments, step (a) occurs less than 30 minutes afterstep (b). In some embodiments, step (a) occurs less than 15 minutesafter step (b).

In some embodiments, the “meal” is any solid food that is consumed thatprovides at least 200 calories to the patient or subject. In otherembodiments, the meal is any solid food that is consumed that providesat least 400 calories to the patient or subject. In yet otherembodiments, the meal is any solid food that is consumed that providesat least 600 calories to the patient or subject. In some embodiments,the meal is a high-fat test meal as described below. In otherembodiments, the meal is a low-fat test meal as described below.

In another aspect, the present disclosure relates to a method ofdelivering a therapeutically effective amount of nilotinib to a patientwithout regard to a food effect, comprising administering atherapeutically effective amount of a pharmaceutical composition of thepresent disclosure to the patient.

In a further aspect, the present disclosure relates to a method ofdelivering a therapeutically effective amount of nilotinib to a patientwithout regard to consumption of food, comprising administering atherapeutically effective amount of a pharmaceutical composition of thepresent disclosure to the patient.

In another aspect, the present disclosure relates to a method ofdelivering a therapeutically effective amount of nilotinib to a patientwithout regard to whether the patient is in a fed state or in a fastedstate, comprising administering a therapeutically effective amount of apharmaceutical composition of the present disclosure to the patient.

As generally interpreted, “food effect” broadly refers to all aspects ofinteractions of food on drug dissolution, absorption, distribution,metabolism and elimination. The implications of food effect includechanges in bioavailability, rate of on-set, duration of therapeuticeffect and incidence and seriousness of side effects. The magnitude of afood effect is generally greatest when the drug product is administeredshortly after a meal is ingested. An example of a drug productexhibiting a food effect is TASIGNA, which as described above canproduce an increase of AUC and C_(max) by 82% and 112%, respectively,when orally taken 30 minutes after a high-fat meal as compared to levelsobtained under fasting conditions.

In practice, a food effect is generally assessed by measuring standardpharmacokinetic parameters observed upon administration of a drugproduct to a subject in a fasted state, versus the same measurementsobserved upon administration to the same subject in a fed state.Relevant pharmacokinetic parameters can include AUC, C_(max), and/orT_(max). AUC can be assessed for a specified time interval (such asAUC_(0-12 h) or AUC_(0-24 h), for example), or as AUC_(0-last) orAUC_(0-inf). Typically, data for a number of test subjects is pooled foranalysis.

For further information about food effect studies, refer to “Guidancefor Industry: Food-Effect Bioavailability and Fed BioequivalenceStudies” (Center for Drug Evaluation and Research (CDER), Food and DrugAdministration (FDA), December 2002), which is hereby incorporated byreference in its entirety. Reference is also made to “Guidance forIndustry: Assessing the Effects of Food on Drugs in INDs andNDAs—Clinical Pharmacology Considerations (Draft Guidance)” (CDER, FDA,February 2019), which is hereby incorporated by reference in itsentirety.

As used in relation to the methods of the present disclosure the phrase“food effect” refers to a relative difference in one or more of AUC,C_(max), and/or T_(max) for an active substance, when said substance ora formulation thereof (such as a solid dispersion or pharmaceuticalcomposition) is administered orally to a human subject, concomitantlywith food or in a fed state, as compared to the measured value for thesame parameter when the same formulation is administered to the samesubject in a fasted state. The food effect F is calculated asF=(Y _(fed) −Y _(fasted))/Y _(fasted)wherein Y_(fed) and Y_(fasted) are the measured values of AUC, C_(max)or T_(max) in the fed and fasted state, respectively.

The phrase “positive food effect” refers to a food effect where the AUCand/or C_(max) is higher when the drug product is administered orally ina fed state than when it is administered in a fasted state. The phrase“negative food effect” refers to a food effect where the AUC and/orC_(max) is lower when the drug product is administered orally in the fedstate than when it is administered in the fasted state.

In assessing food effect, data obtained from fasted and fed studies isprocessed using conventional pharmacokinetic statistical analyses andmethods. Fasted and fed studies may be single-dose studies orsteady-state studies, as appropriate. Using pooled data from a suitablenumber of subjects, an absence of food effect is indicated when the 90%confidence interval for the ratio of population geometric means betweenfed and fasted administrations, based on log-transformed data, iscontained in the equivalence limits of 80% to 125% for AUC_(0-inf) (orAUC_(0-t) when appropriate) and C_(max). On the other hand, an absenceof food effect is not established if the 90% confidence interval for theratio of population geometric means between fed and fastedadministrations, based on log-transformed data, is not contained in theequivalence limits of 80% to 125% for either AUC_(0-inf) (or AUC_(0-t)when appropriate) or C_(max).

In the methods of the present disclosure, “without a food effect” meansthat the relative difference is not substantially large, e.g., less than20%, or less than 15%, or less than 10%, for AUC (which can be, forexample, AUC_(0-24 h), AUC_(0-last) or AUC_(0-inf)) and/or C_(max), fornilotinib when the ASD or pharmaceutical composition of the presentdisclosure is administered orally, concomitantly with food or in a fedstate, as compared to the measured value for the same parameter when thesame ASD or pharmaceutical composition is administered in a fastedstate. (As used herein, for a relative difference stated as apercentage, each stated range is with respect to the absolute value ofthat relative difference; i.e., “less than 20%” means that the relativedifference F falls in the range −20%<F<+20%.)

In the methods of the present disclosure, “without regard to consumptionof food” means that no consideration has to be made whether the ASD orpharmaceutical composition of the present disclosure is beingadministered to the subject or patient concomitantly with food, orwhether the patient or subject is in a fed state or fasted state. Theadministration will be expected to provide a therapeutically relevantexposure, and will not be expected to cause an unsafe overexposure,regardless of whether the patient or subject is in a fed state or fastedstate.

“Therapeutically relevant exposure” as used herein means an exposurethat provides AUC_(0-t) (such as AUC_(0-24 h)) and/or C_(max), in thesubject's plasma that would be expected to produce the desiredtherapeutic effect. One way to determine a similar therapeutic effect isif the AUC₀₋₄ or C_(max) is within the 80% to 125% bioequivalencecriteria compared to administration of an appropriate strength(determined with reference to the product's labeling) of a conventionalimmediate-release nilotinib composition to the same subject or subjects,dosed according to its labeled instructions.

As used herein, the phrase “conventional immediate-release nilotinibcomposition” refers to a commercially available composition comprisingnilotinib monohydrochloride monohydrate, generally in crystalline form.The conventional immediate-release nilotinib composition may be in acapsule dosage form. One suitable conventional immediate-releasenilotinib composition is TASIGNA IR Capsule (marketed in the UnitedStates under New Drug Application 22-068). TASIGNA is understood tocontain crystalline nilotinib monohydrochloride monohydrate in animmediate-release capsule formulation.

The phrase “concomitantly with food,” as used herein, refers toadministration to the subject from 30 minutes after the subject ingestsfood to 1 hour after the subject ingests food. The phrase“administration in a fed state” (or equivalently “administration underfed conditions”) as used herein, refers to administration to the subjectfrom 30 minutes after the subject starts ingesting a meal to 1 hourafter complete ingestion of a meal. Similarly, “fed state” or “fedconditions” refers to the condition of a subject 30 minutes after thesubject starts ingesting a meal to 1 hour after complete ingestion of ameal.

In some embodiments, the meal is a “high-fat test meal” (oralternatively, “high-fat meal”), which in accordance with FDA's Guidancefor Industry (December 2002) referenced above, is a high-fat andhigh-calorie (approximately 800 to 1000 calories) meal comprisingapproximately 150 calories from protein, 250 calories from carbohydrate,and 500-600 calories from fat. In other embodiments, the meal is a“low-fat test meal,” which in accordance with FDA's Draft Guidance forIndustry (February 2019) referenced above, is a lower-calorie(approximately 400 to 500 calories) meal comprising approximately 11-14grams of fat and approximately 25% calories from fat (with the balancefrom protein and carbohydrate).

The phrase “administration in a fasted state” (or equivalently“administration under fasting conditions”) as used herein refers toadministration to the subject at least 2 hours, more suitably at least 4hours, or more suitably at least 8 hours after the subject's previousmeal. Preferably, administration in a fasted state or under fastingconditions follows an overnight fast of at least 10 hours. Similarly,“fasted state” or “fasting conditions,” as used herein, refers to thecondition in which the subject has not eaten for at least two hours,more suitably at least 4 hours, or more suitably at least 8 hours; orthe condition of the subject following an overnight fast of at least 10hours. Moreover, administration in a fasted state or under fastingconditions may also require continued fasting for at least 1 hour, moresuitably at least 2 hours, or more suitably at least 4 hours followingthe administration.

In certain embodiments, the ASD or pharmaceutical composition isadministered without regard to whether the subject is in a fasted state.In certain embodiments, the ASD or pharmaceutical composition isadministered without regard to whether the subject is in a fed state. Incertain embodiments, the ASD or pharmaceutical composition isadministered without regard to whether the subject is in a fasted stateor in a fed state. In certain embodiments, the ASD or pharmaceuticalcomposition is administered without regard to a food effect. In certainembodiments, the ASD or pharmaceutical composition is administeredconcomitantly with food.

Some embodiments relate to a method of delivering nilotinib to a subjectwithout regard to whether the subject is in a fasted state, the methodcomprising administering to the subject an ASD or pharmaceuticalcomposition according to the disclosure.

Some embodiments relate to a method of delivering nilotinib to a subjectwithout regard to whether the subject is in a fed state, the methodcomprising administering to the subject an ASD or pharmaceuticalcomposition according to the disclosure.

Some embodiments relate to a method of delivering nilotinib to a subjectwithout regard to whether the subject is in a fasted state or a fedstate, the method comprising administering to the subject an ASD orpharmaceutical composition according to the disclosure.

Administration of the ASD or pharmaceutical composition of the presentdisclosure can be characterized by the pharmacokinetic profile or bycalculated pharmacokinetic parameters (such as C_(max) and/or AUC_(0-t),which can be, for example, AUC_(0-24 h), AUC_(0-last) or AUC_(0-inf))resulting from the administration of the ASD or pharmaceuticalcomposition at certain dosages to a subject in a fasted state or a fedstate.

For example, in some embodiments, administration to a healthy humansubject in a fasted state of the ASD or pharmaceutical composition ofthe disclosure at a dose of 40 mg to 80 mg nilotinib may result in aplasma C_(max) of nilotinib of 501 ng/mL to 621 ng/mL; a plasmaAUC_(0-12 h) of nilotinib of 3790 ng·h/mL to 4820 ng·h/mL; a plasmaAUC_(0-24 h) of nilotinib of 5590 ng·h/mL to 7340 ng·h/mL; a plasmaAUC_(0-last) of nilotinib of 7610 ng·h/mL to 10600 ng·h/mL; and/or aplasma AUC_(0-inf) of nilotinib of 7760 ng·h/mL to 11000 ng·h/mL.

In some embodiments, administration to a healthy human subject in fedstate of the ASD or pharmaceutical composition of the disclosure at adose of 40 mg to 80 mg nilotinib may result in a plasma C_(max) ofnilotinib of 456 ng/mL to 525 ng/mL; a plasma AUC_(0-12 h) of nilotinibof 3770 ng·h/mL to 4320 ng·h/mL; a plasma AUC_(0-24 h) of nilotinib of6310 ng·h/mL to 7130 ng·h/mL; a plasma AUC_(0-last) of nilotinib of 9490ng·h/mL to 11000 ng·h/mL; and/or a plasma AUC_(0-inf) of nilotinib of9840 ng·h/mL to 11300 ng·h/mL.

Administration of the ASD or pharmaceutical composition of the presentdisclosure can also be characterized by how the pharmacokinetic profileresulting from administration of the ASD or pharmaceutical compositionto a subject in a fed state compares to the pharmacokinetic profileresulting from administration of the ASD or pharmaceutical compositionto a subject in a fasted state. As an example, for some embodiments,administration of the ASD or pharmaceutical composition of the presentdisclosure to a subject in a fed state and in a fasted state may resultin a relative difference in the plasma exposure of nilotinib between thefed state and the fasted state of less than 50%, less than 40%, or lessthan 35%, or less than 30%, or less than 25%, or less than 20%, or lessthan 15%, or less than 10%, or less than 5%. Exposure may be expressedas AUC_(0-12 h), AUC_(0-24 h), AUC_(0-last), or AUC_(0-inf), forexample. Exposure can be demonstrated for an individual subject, oralternatively for a suitable number of subjects (n>1). When comparing anumber of subjects for which data is pooled, the exposure may beexpressed as a population geometric mean, in accordance withconventional pharmacokinetic statistical analyses and methods.

In certain embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fed state mayresult in plasma AUC_(0-12 h) of nilotinib that is less than the plasmaAUC_(0-12 h) of nilotinib that may result from administration of thepharmaceutical composition to the subject in a fasted state. In certainembodiments, administration of the ASD or pharmaceutical composition ofthe present disclosure to a subject in a fed state may result in plasmaAUC_(0-12 h) of nilotinib that is within 25%, or within 20%, of theplasma AUC_(0-12 h) of nilotinib that may result from administration ofthe pharmaceutical composition to the subject in a fasted state. PlasmaAUC_(0-12 h) can be for an individual subject, or a geometric mean froma number of subjects.

In certain embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fed state mayresult in plasma AUC_(0-24 h) of nilotinib that is less than the plasmaAUC_(0-24 h) of nilotinib that may result from administration of thepharmaceutical composition to the subject in a fasted state. In certainembodiments, administration of the ASD or pharmaceutical composition ofthe present disclosure to a subject in a fed state may result in plasmaAUC_(0-24 h) of nilotinib that is within 50%, or within 40%, or within35%, or within 30%, or within 25%, or within 20%, or within 15%, orwithin 10%, of the plasma AUC_(0-24 h) of nilotinib that may result fromadministration of the pharmaceutical composition to the subject in afasted state. Plasma AUC_(0-24 h) can be for an individual subject, or ageometric mean from a number of subjects.

In certain embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fed state mayresult in plasma AUC_(0-last) of nilotinib that is less than the plasmaAUC_(0-last) of nilotinib that may result from administration of thepharmaceutical composition to the subject in a fasted state. In certainembodiments, administration of the ASD or pharmaceutical composition ofthe present disclosure to a subject in a fed state may result in plasmaAUC_(0-last) of nilotinib that is within 50%, or within 40%, or within35%, or within 30%, or within 25%, or within 20%, or within 15%, orwithin 10%, of the plasma AUC_(0-last) of nilotinib that may result fromadministration of the pharmaceutical composition to the subject in afasted state. Plasma AUC_(0-last) can be for an individual subject, or ageometric mean from a number of subjects.

In certain embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fed state mayresult in plasma AUC_(0-inf) of nilotinib that is less than the plasmaAUC_(0-inf) of nilotinib that may result from administration of thepharmaceutical composition to the subject in a fasted state. In certainembodiments, administration of the ASD or pharmaceutical composition ofthe present disclosure to a subject in a fed state may result in plasmaAUC_(0-inf) of nilotinib that is within 50%, or within 40%, or within35%, or within 30%, or within 25%, or within 20%, or within 15%, orwithin 10%, of the plasma AUC_(0-inf) of nilotinib that may result fromadministration of the pharmaceutical composition to the subject in afasted state. Plasma AUC_(0-inf) can be for an individual subject, or ageometric mean from a number of subjects.

For some embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fed state and ina fasted state may result in a relative difference in the plasma C_(max)of nilotinib between the fed state and the fasted state of less than50%, less than 30%, or less than 25%, or less than 20%, or less than15%, or less than 10%, or less than 5%. In certain embodiments,administration of the ASD or pharmaceutical composition of the presentdisclosure to a subject in a fed state may result in plasma C_(max) ofnilotinib that is less than the C_(max) of nilotinib that may resultfrom administration of the ASD or pharmaceutical composition of thepresent disclosure to the subject in a fasted state. C_(max) can bedemonstrated for an individual subject, or alternatively for a suitablenumber of subjects (n>1). When comparing a number of subjects for whichdata is pooled, the C_(max) may be expressed as a population geometricmean, in accordance with conventional pharmacokinetic statisticalanalyses and methods.

In yet other embodiments, administration of the ASD or pharmaceuticalcomposition to a subject in a fed state provides an exposure ofnilotinib that is similar to the exposure resulting from administrationof the pharmaceutical composition to the subject in a fasted state.Exposure may be expressed as AUC_(0-12 h), AUC_(0-24 h), AUC_(0-last),or AUC_(0-inf), for example; exposure can be for an individual subject,or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition to a subject in a fed state provides a plasma C_(max) ofnilotinib that is similar to the plasma C_(max) of nilotinib resultingfrom administration of the ASD or pharmaceutical composition to thesubject in a fasted state. Plasma C_(max) can be for an individualsubject, or a geometric mean from a number of subjects.

As used herein in this context, “similar” exposure means a relativedifference in the plasma exposure of nilotinib between the fed state andthe fasted state of less than 25%, or less than 20%, or less than 15%,or less than 10%, or less than 5%; and “similar” C_(max) likewise meansa relative difference in the plasma C_(max) of nilotinib between the fedstate and the fasted state of less than 25%, or less than 20%, or lessthan 15%, or less than 10%, or less than 5% (each stated percentage isunderstood to be an absolute value; i.e., “less than 20%” means that therelative difference F falls in the range −20%<F<+20%).

In some embodiments, the pharmaceutical composition of the presentdisclosure may provide a plasma C_(max) of nilotinib of 501 ng/mL to 621ng/mL resulting from administration of a dose of 40 mg to 80 mgnilotinib to a healthy human subject in a fasted state, and may providea plasma C_(max) of nilotinib of 456 ng/mL to 525 ng/mL resulting fromadministration of a dose of 40 mg to 80 mg nilotinib to a healthy humansubject in fed state.

In some embodiments, the pharmaceutical composition of the presentdisclosure may provide a plasma AUC_(0-12 h) of nilotinib of 3790ng·h/mL to 4820 ng·h/mL resulting from administration of a dose of 40 mgto 80 mg nilotinib to a healthy human subject in a fasted state, and mayprovide a plasma AUC_(0-12 h) of nilotinib of 3770 ng·h/mL to 4320ng·h/mL resulting from administration of a dose of 40 mg to 80 mgnilotinib to a healthy human subject in fed state.

In some embodiments, the pharmaceutical composition of the presentdisclosure may provide a plasma AUC_(0-24 h) of nilotinib of 5590ng·h/mL to 7340 ng·h/mL resulting from administration of a dose of 40 mgto 80 mg nilotinib to a healthy human subject in a fasted state, and mayprovide a plasma AUC_(0-24 h) of nilotinib of 6310 ng·h/mL to 7130ng·h/mL resulting from administration of a dose of 40 mg to 80 mgnilotinib to a healthy human subject in fed state.

In some embodiments, the pharmaceutical composition of the presentdisclosure may provide a plasma AUC_(0-last) of nilotinib of 7610ng·h/mL to 10600 ng·h/mL resulting from administration of a dose of 40mg to 80 mg nilotinib to a healthy human subject in a fasted state, andmay provide a plasma AUC_(0-last) of nilotinib of 9490 ng·h/mL to 11000ng·h/mL resulting from administration of a dose of 40 mg to 80 mgnilotinib to a healthy human subject in fed state.

In some embodiments, the pharmaceutical composition of the presentdisclosure may provide a plasma AUC_(0-inf) of nilotinib of 7760 ng·h/mLto 11000 ng·h/mL resulting from administration of a dose of 40 mg to 80mg nilotinib to a healthy human subject in a fasted state, and mayprovide a plasma AUC_(0-inf) of nilotinib of 9840 ng·h/mL to 11300ng·h/mL resulting from administration of a dose of 40 mg to 80 mgnilotinib to a healthy human subject in fed state.

As used herein, the phrase “food-insensitive composition” indicates apharmaceutical composition of the present disclosure that can beadministered without regard to the patient's or subject's fed or fastedstate. A food-insensitive composition provides a therapeuticallyrelevant exposure to the patient or subject regardless of whether thepatient or subject has recently ingested a meal, or whether the patientor subject ingests a meal shortly after administration of thepharmaceutical composition, or whether the patient or subject was in afasted state at the time of administration and remains in the fastedstate for some time following administration. In some embodiments, thefood-insensitive composition is an orally disintegrating tablet asdescribed herein.

Methods of Administering at Reduced Dosage

In addition, administration of the ASD or pharmaceutical composition ofthe present disclosure can be characterized by how the pharmacokineticprofile resulting from administration of the ASD or pharmaceuticalcomposition compares to the pharmacokinetic profile resulting fromadministration of a conventional immediate-release nilotinibcomposition.

For instance, in some embodiments, administration of an ASD orpharmaceutical composition of the present disclosure may result in apharmacokinetic profile that is comparable to the pharmacokineticprofile obtained by orally administering a conventionalimmediate-release nilotinib formulation, but administered at a fractionof the dosage. For this comparison, administration must be done in afasted state, since TASIGNA should only be administered in a fastedstate.

For embodiments of the disclosure that can be administered at a fractionof the dosage as compared to the dosage required when administering aconventional immediate-release nilotinib composition, it can be reasonedthat the inventive formulation is inherently safer than thecorresponding conventional immediate-release nilotinib composition. Bydecreasing the required dosage while still providing an efficaciousexposure to the patient, the risks of overexposure are reduced.Overexposure to nilotinib is associated with the risk of QT prolongationdiscussed above, which is currently the subject of a “black box warning”on the TASIGNA label. The risk of overexposure affects the entirepatient population treated with nilotinib. As such, a reduced dosageinherently decreases the risk of sudden death in the patient population,since QT prolongation is reported to cause sudden cardiac death inapproximately one out of every 300 TASIGNA patients.

In addition to reducing the overall risk of overexposure, theformulations of the disclosure may limit risk associated with anundesirably high C_(max). For certain risks such as QT prolongation,C_(max) may in fact be the more relevant pharmacokinetic parameter. Asizable increase in C_(max), such as between fasted and fed states, maybe highly undesirable and potentially unsafe. In some embodiments, theformulations of the disclosure reduce or eliminate the possibility thata patient may experience an undesirably high C_(max).

With respect to the respective pharmacokinetic profiles, by“comparable,” it is meant that the administration of the ASD or thepharmaceutical composition of the disclosure to the subject may provideAUC_(0-t) (such as AUC_(0-24 h) or AUC_(0-inf)) or C_(max) in thesubject's plasma that are within the 80% to 125% bioequivalence criteriacompared to administration of the immediate-release crystallinenilotinib formulation to the same subject, dosed according to itslabeled instructions.

As used herein, “fraction of the dosage” may mean that the dose ofnilotinib in the ASD or pharmaceutical composition of the presentdisclosure may be 80% less, or 75% less, or 70% less, or 65% less, or60% less, or 55% less, or 50% less, or 45% less, or 40% less, or 35%less, or 30% less, or 25% less, or 20% less, as compared to the labeleddosage of the immediate-release crystalline nilotinib formulation.

By way of example only, a pharmaceutical composition of the presentdisclosure containing approximately 50 mg nilotinib free base mayprovide a pharmacokinetic profile that is comparable to thepharmacokinetic profile obtained by orally administering animmediate-release crystalline nilotinib formulation labeled to contain200 mg of nilotinib (such as 200 mg TASIGNA IR Capsule). In thisexample, the dose of nilotinib in the inventive pharmaceuticalcomposition is 75% less than the dosage of the immediate-releasecrystalline nilotinib formulation.

In some embodiments, the dose of nilotinib in the ASD or pharmaceuticalcomposition of the present disclosure is at least 80% less, or 75% less,or 70% less, or 65% less, or 60% less, or 55% less, or 50% less, ascompared to the labeled dosage of the immediate-release crystallinenilotinib formulation.

For some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma exposure of nilotinib that is within 20%, or within15%, or within 10%, of the plasma exposure of nilotinib that may resultfrom administration to a subject in a fasted state of animmediate-release crystalline nilotinib formulation, where the ASD orpharmaceutical composition is administered at a fraction of the dosage.In certain embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma exposure of nilotinib that is greater than the plasmaexposure of nilotinib that may result from administration to a subjectin a fasted state of an immediate-release crystalline nilotinibformulation, where the ASD or pharmaceutical composition is administeredat a fraction of the dosage. Exposure may be expressed as AUC_(0-12 h),AUC_(0-24 h), AUC_(0-last), or AUC_(0-inf), for example. Exposure can befor an individual subject, or a geometric mean from a number ofsubjects.

For some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma C_(max) of nilotinib that is within 20%, or within 15%,or within 10%, of the plasma C_(max) of nilotinib that may result fromadministration to a subject in a fasted state of an immediate-releasecrystalline nilotinib formulation, where the ASD or pharmaceuticalcomposition is administered at a fraction of the dosage. In certainembodiments, administration of the ASD or pharmaceutical composition ofthe present disclosure to a subject in a fasted state may result inplasma C_(max) of nilotinib that is greater than the plasma C_(max) ofnilotinib that may result from administration to a subject in a fastedstate of an immediate-release crystalline nilotinib formulation, wherethe ASD or pharmaceutical composition is administered at a fraction ofthe dosage. C_(max) can be for an individual subject, or a geometricmean from a number of subjects.

In the practice of some embodiments, the dosage of immediate-releasecrystalline nilotinib formulation is a multiple of the dose of thenilotinib contained in the pharmaceutical composition according to thedisclosure. In some embodiments, the immediate-release crystallinenilotinib formulation may comprise at least two times, at least threetimes, at least four times, or at least five times, the amount ofnilotinib as the pharmaceutical composition according to the disclosure.In some embodiments, the immediate-release crystalline nilotinibformulation may comprise from two times to five times the amount ofnilotinib as the pharmaceutical composition according to the disclosure.In some embodiments, the immediate-release crystalline nilotinibformulation may comprise from two times to four times the amount ofnilotinib as the pharmaceutical composition according to the disclosure.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma AUC_(0-12 h) of nilotinib that is greater than theplasma AUC_(0-12 h) of nilotinib that may result from the administrationof an immediate-release crystalline nilotinib formulation that has fourtimes, or three times, or twice, the amount of nilotinib as the ASD orpharmaceutical composition. Plasma AUC_(0-12 h) can be for an individualsubject, or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma AUC_(0-12 h) of nilotinib that is within 20%, or within15%, of the plasma AUC_(0-12 h) of nilotinib that may result from theadministration of an immediate-release crystalline nilotinib formulationthat has four times, or three times, or twice, the amount of nilotinibas the ASD or pharmaceutical composition. Plasma AUC_(0-12 h) can be foran individual subject, or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma AUC_(0-24 h) of nilotinib that is greater than theplasma AUC_(0-24 h) of nilotinib that may result from the administrationof an immediate-release crystalline nilotinib formulation that has fourtimes, or three times, or twice, the amount of nilotinib as the ASD orpharmaceutical composition. Plasma AUC_(0-24 h) can be for an individualsubject, or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma AUC_(0-24 h) of nilotinib that is within 20%, or within15%, of the plasma AUC_(0-24 h) of nilotinib that may result from theadministration of an immediate-release crystalline nilotinib formulationthat has four times, or three times, or twice, the amount of nilotinibas the ASD or pharmaceutical composition. Plasma AUC_(0-24 h) can be foran individual subject, or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma AUC_(0-last) of nilotinib that is within 20%, or within15%, of the plasma AUC_(0-last) of nilotinib that may result from theadministration of an immediate-release crystalline nilotinib formulationthat has four times, or three times, or twice, the amount of nilotinibas the ASD or pharmaceutical composition. Plasma AUC_(0-last) can be foran individual subject, or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma AUC_(0-inf) of nilotinib that is within 25%, or within20%, of the plasma AUC_(0-inf) of nilotinib that may result from theadministration of an immediate-release crystalline nilotinib formulationthat has four times, or three times, or twice, the amount of nilotinibas the ASD or pharmaceutical composition. Plasma AUC_(0-inf) can be foran individual subject, or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma C_(max) of nilotinib that is greater than the plasmaC_(max) of nilotinib that may result from the administration of animmediate-release crystalline nilotinib formulation that has four times,or three times, or twice, the amount of nilotinib as the ASD orpharmaceutical composition. Plasma C_(max) can be for an individualsubject, or a geometric mean from a number of subjects.

In some embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted state mayresult in plasma C_(max) of nilotinib that is within 25%, or within 20%,of the plasma C_(max) of nilotinib that may result from theadministration of an immediate-release crystalline nilotinib formulationthat has four times, or three times, or twice, the amount of nilotinibas the ASD or pharmaceutical composition. Plasma C_(max) can be for anindividual subject, or a geometric mean from a number of subjects.

In yet other embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted stateprovides an exposure of nilotinib that is similar to the exposureresulting from administration of an immediate-release crystallinenilotinib formulation, but administered at a fraction of the dosage.Exposure may be expressed as AUC_(0-12 h), AUC_(0-24 h), AUC_(0-last),or AUC_(0-inf), for example; exposure can be for an individual subject,or a geometric mean from a number of subjects.

In yet other embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fasted stateprovides plasma C_(max) of nilotinib that is similar to the plasmaC_(max) of nilotinib resulting from administration of animmediate-release crystalline nilotinib formulation, but administered ata fraction of the dosage. Plasma C_(max) can be for an individualsubject, or a geometric mean from a number of subjects.

In yet other embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fed stateprovides an exposure of nilotinib that is similar to the exposureresulting from administration of an immediate-release crystallinenilotinib formulation to the subject in a fasted state, but administeredat a fraction of the dosage. Exposure may be expressed as AUC_(0-12 h),AUC_(0-24 h), AUC_(0-last), or AUC_(0-inf), for example; exposure can befor an individual subject, or a geometric mean from a number ofsubjects.

In yet other embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject in a fed stateprovides plasma C_(max) of nilotinib that is similar to the plasmaC_(max) of nilotinib resulting from administration of animmediate-release crystalline nilotinib formulation to the subject in afasted state, but administered at a fraction of the dosage. PlasmaC_(max) can be for an individual subject, or a geometric mean from anumber of subjects.

As used herein in this context, “similar” exposure means a relativedifference in the plasma exposure of nilotinib between administration ofthe pharmaceutical composition and administration of theimmediate-release crystalline nilotinib formulation, of less than 25%,or less than 20%, or less than 15%, or less than 10%, or less than 5%;and “similar C_(max)” means a relative difference in the plasma C_(max)of nilotinib between administration of the pharmaceutical compositionand administration of the immediate-release crystalline nilotinibformulation, of less than 25%, or less than 20%, or less than 15%, orless than 10%, or less than 5% (each stated percentage is understood tobe an absolute value; i.e., “less than 20%” means that the relativedifference F falls in the range −20%<F<+20%).

Effective Bioequivalence to Reference Composition

In another aspect, the disclosure provides pharmaceutical compositionsthat are effectively bioequivalent to a suitable reference compositionwhen administered to healthy human subjects in a fasted state, but at alower molar dose of the active ingredient as compared to the referencecomposition. In some embodiments, the reference composition is aconventional immediate-release nilotinib composition comprisingnilotinib monohydrochloride monohydrate. In some embodiments, thereference composition is TASIGNA IR Capsule.

Pertaining to bioequivalence studies, FDA has published “Guidance forIndustry: Bioequivalence Studies with Pharmacokinetic Endpoints forDrugs Submitted Under an ANDA (Draft Guidance)” (CDER, FDA, December2013), which is hereby incorporated by reference in its entirety.Pertaining to statistical methods for determining bioequivalence, FDAhas published “Guidance for Industry: Statistical Approaches toEstablishing Bioequivalence” (CDER, FDA, January 2001), which is herebyincorporated by reference in its entirety.

Per FDA guidelines, a drug product (a “test composition”) isbioequivalent to a reference drug product (the “reference composition”)when the rate and extent of absorption of the drug substance (i.e., theactive ingredient) from the test composition do not show a significantdifference from the rate and extent of absorption of the drug substancewhen administered using the reference composition, under similarexperimental conditions. For many drug substances that are orallybioavailable, including nilotinib, the preferred method for assessingbioequivalence is by assessing the pharmacokinetic profile attained uponoral administration of the test and reference compositions.

The bioequivalence assessment frequently relies on pharmacokineticendpoints such as C_(max) and AUC that are reflective of rate and extentof absorption, respectively. Generally speaking, using pooled data froma suitable number of subjects, bioequivalence between the testcomposition and reference composition is established when the 90%confidence interval (“CI”) for the ratio of population geometric meansbetween test composition and reference composition administrations,based on log-transformed data, is contained in the equivalence limits of80% to 125% for both AUC_(0-inf) (or AUC_(0-t) when appropriate) andC_(max). On the other hand, bioequivalence is not established if the 90%confidence interval for the ratio of population geometric means betweentest composition and reference composition administrations, based onlog-transformed data, is not contained in the equivalence limits of 80%to 125% for either AUC_(0-inf) (or AUC_(0-t) when appropriate) orC_(max).

As discussed above, a pharmacokinetic profile is assessed by monitoringthe subject's blood plasma over time for the presence of the activeingredient (or in some cases a suitable surrogate, such as a metabolite)after administration of the pharmaceutical composition of interest. Perthe FDA draft guidance for nilotinib hydrochloride monohydratecompositions, the plasma analyte of interest is nilotinib. Nilotinib isalso the relevant plasma analyte for the pharmaceutical compositions ofthe present disclosure.

Depending on the nature of the drug substance and the reference and testcompositions, the required showing may require single-dose ormultiple-dose studies. The most recent FDA guidance document (draftguidance, July 2014) on bioequivalence studies pertaining to nilotinibhydrochloride monohydrate oral capsules (200 mg) recommend a single-dosetwo-way crossover study under fasting conditions.

Per FDA guidelines, a test composition can only be bioequivalent whendosed at the same molar dose of the active ingredient as the referencecomposition. As discussed above, however, administration of an ASD orpharmaceutical composition of the present disclosure may result in apharmacokinetic profile that is comparable to the pharmacokineticprofile obtained by orally administering a conventionalimmediate-release nilotinib formulation, but administered at a fractionof the dosage. For such embodiments, a more appropriate comparison is toassess the relative bioavailability when the test composition is dosedat a fraction of the corresponding molar dose of the chosen referencecomposition. As used herein, the phrases “effectively bioequivalent” and“effective bioequivalence” are used to refer to the situation where atest composition and reference composition meet stated bioequivalencecriteria, but at different molar doses.

In one embodiment, the disclosure provides a pharmaceutical compositioncomprising 100 mg nilotinib in an oral dosage form; wherein, when theoral dosage form is administered to a healthy human subjects in a fastedstate, achieves an AUC_(0-inf) and C_(max) within the 80% to 125%bioequivalence criteria as compared to AUC_(0-inf) and C_(max) achievedupon administration of a reference composition, wherein the referencecomposition is a conventional immediate-release nilotinib compositioncomprising 200 mg nilotinib monohydrochloride monohydrate.

In another embodiment, the disclosure provides a pharmaceuticalcomposition comprising an amorphous solid dispersion including nilotiniband one or more polymers, wherein the composition is contained in anoral dosage form comprising 100 mg nilotinib; and wherein, when the oraldosage form is administered to a healthy human subjects in a fastedstate, achieves an AUC_(0-inf) and C_(max) within the 80% to 125%bioequivalence criteria as compared to AUC_(0-inf) and C_(max) achievedupon administration of a reference composition, wherein the referencecomposition is conventional immediate-release nilotinib compositioncomprising 200 mg nilotinib monohydrochloride monohydrate.

In another embodiment, the disclosure provides a pharmaceuticalcomposition comprising 100 mg nilotinib in an oral dosage form, whereinthe pharmaceutical composition is effectively bioequivalent underfasting conditions to a reference composition which is a conventionalimmediate-release nilotinib composition comprising 200 mg nilotinibmonohydrochloride monohydrate; where effective bioequivalence isestablished by: (a) a 90% confidence interval for AUC which is between80% and 125%; and (b) a 90% confidence interval for C_(max), which isbetween 80% and 125%.

In another aspect, the disclosure provides pharmaceutical compositionsthat meet one or more bioequivalence criteria when administered tohealthy human subjects in either a fasted or fed state, as compared to asuitable reference composition when administered to healthy humansubjects in a fasted state, but at a lower molar dose of the activeingredient as compared to the reference composition.

In any of the foregoing embodiments, the AUC can be AUC_(0-24 h),AUC_(0-last), or AUC_(0-inf), for example, as appropriate.

In some embodiments, the reference composition is a conventionalimmediate-release nilotinib composition comprising nilotinibmonohydrochloride monohydrate. In some embodiments, the referencecomposition comprises crystalline nilotinib monohydrochloridemonohydrate. In some embodiments, the reference composition is incapsule form. In some embodiments, the reference composition is TASIGNAIR Capsule.

In some embodiments, the oral dosage form is an orally disintegratingtablet as described herein.

Methods of Co-Administering with a Gastric Acid-Reducing Agent

Other embodiments of the present disclosure relate to the use of thenilotinib ASDs and the pharmaceutical compositions of the presentdisclosure with a gastric acid-reducing agent.

In one aspect, the present disclosure relates to a method of deliveringnilotinib concurrently with a gastric acid-reducing agent to a patientin need thereof, comprising co-administering to the patient (a) atherapeutically effective amount of a pharmaceutical composition of thepresent disclosure, and (b) a therapeutically effective amount of thegastric acid-reducing agent.

In another aspect, the present disclosure relates to a method oftreating a patient who has a proliferative disorder and is sufferingfrom condition caused by the overproduction of stomach acid orexacerbated by stomach acid, the method comprising co-administering tothe patient (a) a therapeutically effective amount of a pharmaceuticalcomposition of the present disclosure, and (b) a therapeuticallyeffective amount of a gastric acid-reducing agent.

In yet another aspect, the present disclosure relates to a method ofdelivering a therapeutically effective amount of nilotinib to a patientwithout regard to whether the patient is concurrently administered agastric acid-reducing agent, comprising administering a therapeuticallyeffective amount of a pharmaceutical composition of the presentdisclosure to the patient.

“Gastric acid-reducing agent” refers herein to any agent that acts tosignificantly reduce the amount of acid in a subject's stomach. Acidreduction can be due to suppression or blocking of acid secretion, or byneutralization of stomach acid. Examples of gastric acid-reducing agentsinclude, but are not limited to, proton pump inhibitors, histamine-2receptor antagonists (or H₂ antagonists), and antacids.

Proton pump inhibitors reduce stomach acid production by blocking thehydrogen/potassium adenosine triphosphatase enzyme (i.e., the gastricproton pump) of the parietal cells, which are the epithelial cells thatsecrete stomach acid. Examples of proton pump inhibitors include, butare not limited to, rabeprazole, esomeprazole, lansoprazole, omeprazole,pantoprazole, and dexlansoprazole.

H₂ antagonists block histamine from binding to the H₂ receptors ofparietal cells, thereby suppressing both the normal secretion andmeal-stimulated secretion of acid by parietal cells. Examples of H₂antagonists include, but are not limited to, famotidine, cimetidine,nizatidine, and ranitidine.

Antacids contain alkaline ions that chemically neutralize stomachgastric acid. Examples of antacids include, but are not limited to,aluminum hydroxide, magnesium hydroxide, sodium citrate, sodiumcarbonate, sodium bicarbonate, calcium carbonate, and magnesiumtrisilicate.

The gastric acid-reducing agent may be administered in accordance withthe dosing information that is known in the art for the agent, oraccording to a physician's instructions. A “therapeutically effectiveamount” of the gastric acid-reducing agent may be the amount set forthin the dosing information that is known in the art for the gastricacid-reducing agent, or according to a physician's instructions. A“standard dosage” is a dosage in accordance with a product's labeledinstructions. In particular, a standard dosage is appropriate forgastric acid-reducing agents that are available over-the-counter (i.e.,without a physician's prescription), such as most antacids, certain H₂antagonists, and certain proton pump inhibitors.

As used herein, a condition caused by the overproduction of stomach acidor exacerbated by stomach acid may be any condition that can be treatedby reducing the amount of acid or the acidity in the subject's stomach.Examples of such a condition include, but are not limited to, dyspepsia(i.e., indigestion), gastroesophageal reflux disease, duodenal orstomach ulcers, erosive esophagitis, stress gastritis, Barrett'sesophagus, and gastrinomas.

As used herein, “co-administration” (or “co-administered”) refers to theadministration of two or more therapeutic agents within a relevantperiod of time (such as one day, or 12 hours, or 8 hours, or 6 hours,for example), such that consideration must be given to whether theadministration of one of the therapeutic agents may affect theabsorption or efficacy of the other. Such administration may be for thetreatment of two or more conditions simultaneously, such as, by way ofexample only, a patient requiring treatment for a proliferative disorderas described herein with nilotinib as a therapeutic agent, while alsobeing treated for another condition, such as acid reflux or ulcers, witha second therapeutic agent such as a gastric acid-reducing agent (e.g.,a proton pump inhibitor). Since both therapeutic agents are dosed atleast once daily, the two therapeutic agents are “co-administered,” andconsideration must be given to whether the administration of one of thetherapeutic agents may affect the absorption or efficacy of the other.

In the context of the present disclosure, the phrase “can beco-administered” means that the two (or more) therapeutic agents ofinterest can be co-administered without a detrimental reduction in theexposure of nilotinib. “Without a detrimental reduction” indicates thatthe realized exposure would be comparable to the exposure realized whenthe gastric acid-reducing agent is not co-administered. Any differencein the realized exposure would be insubstantial and/or therapeuticallyinconsequential. In contrast, when a detrimental reduction in exposurewould be realized, then co-administration should be avoided. A“detrimental reduction” means a substantial and material reduction inthe realized exposure. By way of example, if the realized exposure wouldbe less than or equal to a level recognized as a sub-therapeuticexposure, then the co-administration would result in a detrimentalreduction in exposure.

As used herein, the phrase “gastric acid-insensitive composition”indicates a pharmaceutical composition of the present disclosure thatcan be administered without regard to the patient or subject's gastricpH. A gastric acid-insensitive composition provides a therapeuticallyrelevant exposure to the patient or subject across a range of gastric pHvalues. Accordingly, a gastric acid-insensitive composition can beadministered whether or not the patient or subject has ingested agastric acid-reducing agent, or whether or not the patient has acondition that causes elevated gastric pH (as further discussed below).In some embodiments, the gastric acid-insensitive composition is anorally disintegrating tablet as described herein.

Embodiments of the disclosure relate to administering a gastricacid-reducing agent shortly before, concurrently with, or shortly afterthe nilotinib ASDs or pharmaceutical compositions of the disclosure. Theterm “shortly before” as used herein may mean that a gastricacid-reducing agent was administered to the subject 10 hours or less, or8 hours or less, or 6 hours or less, or 5 hours or less, or 4 hours orless, or 3 hours or less, or 2 hours or less, or 1 hour or less, or 45minutes or less, or 30 minutes or less, or 15 minutes or less, prior tothe administration of the pharmaceutical composition of the disclosure.The term “concurrently” or “concomitantly” as used herein may mean thata gastric acid-reducing agent was administered to the subject within 30minutes or less, or within 20 minutes or less, or within 15 minutes orless, or within 10 minutes or less, or within 5 minutes or less, orwithin 4 minutes or less, or within 3 minutes or less, or within 2minutes or less, or within 1 minute or less, or simultaneously, of theadministration of the pharmaceutical composition. The term “shortlyafter” as used herein means that a gastric acid-reducing agent wasadministered to the subject 6 hours or less, or 5 hours or less, or 4hours or less, or 3 hours or less, or 2 hours or less, or 1 hour orless, or 45 minutes or less, or 30 minutes or less, or 15 minutes orless, after the administration of the pharmaceutical composition.

In some embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject who was concurrently,shortly before, or shortly after administered a gastric acid-reducingagent exhibits a pharmacokinetic profile of nilotinib that is similar tothe pharmacokinetic profile resulting from administration of the ASD orpharmaceutical composition to a subject who was not concurrently,shortly before, or shortly after administered a gastric acid-reducingagent. In certain embodiments, single administration of the ASD orpharmaceutical composition to a subject who was concurrently, shortlybefore, or shortly after administered a gastric acid-reducing agentresults in an AUC of nilotinib that is within 50%, or within 40%, orwithin 30%, of the AUC of nilotinib that results from administration ofthe ASD or pharmaceutical composition without being administered thegastric acid-reducing agent concurrently, shortly before, or shortlyafter. In certain embodiments, the AUC is AUC_(0-24 h). In otherembodiments, the AUC is AUC_(0-inf).

Aspects of the present disclosure further relate to treatment regimensinvolving the administration of pharmaceutical composition of thedisclosure, and a gastric acid-reducing agent. Such treatment regimensmay be for treating a proliferative disorder in a patient in needthereof, or for treating a proliferative disorder and a condition causedby the overproduction of stomach acid or exacerbated by stomach acid ina patient in need thereof.

In some embodiments, the treatment regimen may comprise (a)administering to the patient a first dose, the first dose comprising atherapeutically effective amount of a proton pump inhibitor; and (b)within 2 hours after the first dose, administering a second dose to thepatient, the second dose comprising a pharmaceutical composition of thepresent disclosure. In certain embodiments, the treatment regimen maycomprise (a) administering to the patient a first dose, the first dosecomprising a therapeutically effective amount of a proton pumpinhibitor; and (b) concurrently administering a second dose to thepatient, the second dose comprising a pharmaceutical composition of thepresent disclosure.

In some embodiments, the treatment regimen may comprise (a)administering to the patient a first dose, the first dose comprising atherapeutically effective amount of an H₂ antagonist; and (b) within 10hours after the first dose, administering a second dose to the patient,the second dose comprising a pharmaceutical composition of the presentdisclosure. In some embodiments, the treatment regimen may comprise (a)administering to the patient a first dose, the first dose comprising apharmaceutical composition of the present disclosure; and (b) within 2hours after the first dose, administering a second dose to the patient,the second dose comprising a therapeutically effective amount of an H₂antagonist.

In some embodiments, the treatment regimen may comprise (a)administering to the patient a first dose, the first dose comprising atherapeutically effective amount of an antacid; and (b) within 2 hoursafter the first dose, administering a second dose to the patient, thesecond dose comprising a pharmaceutical composition of the presentdisclosure. In some embodiments, the treatment regimen may comprise (a)administering to the patient a first dose, the first dose comprising apharmaceutical composition of the present disclosure; and (b) within 2hours after the first dose, administering a second dose to the patient,the second dose comprising a therapeutically effective amount of anantacid.

Methods of Treating a Patient Having Elevated Gastric pH

The pharmaceutical compositions of the present disclosure may besuitably administered to subjects or patients with an elevated gastricpH.

One aspect of the present disclosure relates to the use of the nilotinibASDs or pharmaceutical compositions of the present disclosure to delivernilotinib to a subject or patient with elevated gastric pH. Someembodiments relate to a method of delivering nilotinib to a subject withelevated gastric pH, the method comprising administering the ASD orpharmaceutical composition of the present disclosure to the subject orpatient. Some embodiments relate to a use of a nilotinib ASD orpharmaceutical composition of the present disclosure for deliveringnilotinib to a subject or patient with elevated gastric pH, the usecomprising administering the ASD or pharmaceutical composition to thesubject or patient. Some embodiments relate to a nilotinib ASD orpharmaceutical composition of the present disclosure for use indelivering nilotinib to a subject or patient with elevated gastric pH,the use comprising administering the ASD or pharmaceutical compositionto the subject or patient. Some embodiments relate to a use of anilotinib ASD or pharmaceutical composition of the present disclosure inthe manufacture of a medicament for delivering nilotinib to a subject orpatient with elevated gastric pH, the delivery comprising administeringthe ASD or pharmaceutical composition to the subject or patient.

As used herein, “gastric pH” refers to the pH inside a subject's orpatient's stomach. Gastric pH may be considered as “elevated” when it isgreater than 3.5, or greater than 4, or greater than 5, measured underfasting conditions. Gastric pH can be evaluated using standard methods,or an elevated gastric pH can be inferred from the known effects of, forexample, treatment with gastric acid-reducing agents or an identifiedcondition that regularly leads to a measurable elevated gastric pH.

In the practice of the present disclosure, subject or patient may havean elevated gastric pH due to different reasons, including, but notlimited to, the subject or patient was administered a gastricacid-reducing agent, or the subject or patient may have a condition thatleads to elevated gastric pH. Elevated gastric pH can result fromconditions such as hypochlorhydria or achlorhydria, or infection byHelicobacter pylori (H. pylori) bacteria, for example.

As used herein, the phrase “chronically elevated” in reference togastric pH means that the subject or patient experiences elevatedgastric pH on a persistent or recurring basis. Chronically elevatedgastric pH can result from, for example, conditions such ashypochlorhydria or achlorhydria, or infection by Helicobacter pyloribacteria.

In some embodiments, the methods of the disclosure may contain a step ofidentifying a condition by which the patient's gastric pH is elevated(including conditions by which it is chronically elevated). Such a stepmay comprise diagnosing the underlying cause of the elevated gastric pH.It is known in medical practice how to diagnose hypochlorhydria orachlorhydria in patient, or how to test for a Helicobacter pyloribacteria infection. Hypochlorhydria or achlorhydria can be diagnosed,for example, by measuring stomach acid levels under differentconditions. Helicobacter pylori bacterial infection can be diagnosed byan appropriate blood test, stool test, breath test, or scope test, forexample.

In some embodiments, the nilotinib ASD or pharmaceutical composition maybe administered to a subject or patient without regard to gastric pH.Thus, the subject or patient may be administered the nilotinib ASD orpharmaceutical composition no matter whether the subject or patient hasnormal gastric pH (i.e., gastric pH below 3.5, generally in the range1.5 to 3) or has elevated gastric pH as described herein. This isbeneficial when, for example, the subject or patient has gastric pH thatfluctuates due to irregular or episodic use of gastric acid-reducingagents, or if the subject or patient has hypochlorhydria (resulting in agastric pH that may fluctuate depending on factors such as whether thesubject or patient has recently eaten).

In some embodiments, administration of an ASD or pharmaceuticalcomposition of the present disclosure to a subject or patient who haselevated gastric pH exhibits a pharmacokinetic profile for nilotinibthat is similar to the pharmacokinetic profile resulting fromadministration of the ASD or pharmaceutical composition to a subject orpatient who has normal gastric pH. In certain embodiments, singleadministration of the ASD or pharmaceutical composition to a subject orpatient with elevated gastric pH results in AUC_(0-t) (such asAUC_(0-24 h), AUC_(0-last) or AUC_(0-inf)) and/or C_(max) of nilotinibthat is within 50%, or within 40%, or within 30%, of the AUC_(0-t)and/or C_(max) of nilotinib that results from single administration ofthe ASD or pharmaceutical composition to a subject or patient withnormal gastric pH. In certain embodiments, the AUC_(0-t) isAUC_(0-24 h). In other embodiments, the AUC_(0-t) is AUC_(0-inf).

In certain embodiments, administration of the ASD or pharmaceuticalcomposition of the present disclosure in a subject or patient withelevated gastric pH may provide AUC_(0-t) (such as AUC_(0-24 h),AUC_(0-last) or AUC_(0-inf)) and C_(max) in the subject's or patient'splasma that are within the 80% to 125% bioequivalence criteria comparedto administration of a conventional immediate-release nilotinibcomposition dosed to subjects or patients with normal gastric pH. Incertain embodiments, the AUC_(0-t) is AUC_(0-24 h). In otherembodiments, the AUC_(0-t) is AUC_(0-inf).

In the practice of the present disclosure, administration of an ASD or apharmaceutical composition can provide enhanced exposure as compared tostandard immediate-release compositions. In some embodiments, singleadministration of an ASD or pharmaceutical composition of the presentdisclosure to a subject or patient who has elevated gastric pH exhibitsgreater AUC and/or C_(max) as compared to single administration of aconventional immediate-release composition of nilotinib (e.g., TASIGNA)to a subject or patient who has elevated gastric pH. (It should beunderstood that the same molar quantity or “label claim” of nilotinib isadministered in each case.) In certain embodiments, the AUC isAUC_(0-24 h). In other embodiments, the AUC is AUC_(0-inf). In certainembodiments, single administration of the ASD or pharmaceuticalcomposition to a subject or patient with elevated gastric pH results inAUC_(0-t) and/or C_(max) of nilotinib that is at least 80% greater, orat least 100% greater, or at least 150% greater, or at least 200%greater, than the AUC_(0-t) and/or C_(max) of nilotinib that resultsfrom administration of a conventional immediate-release composition ofnilotinib to the subject or patient with elevated gastric pH. In certainembodiments, the AUC_(0-t) is AUC_(0-24 h). In other embodiments, theAUC_(0-t) is AUC_(0-inf).

Further, one aspect of the present disclosure relates to the use of thenilotinib ASDs or pharmaceutical compositions of the present disclosureto deliver nilotinib to a subject without regard to the subject'sgastric pH. Some embodiments relate to a method of delivering nilotinibto a subject without regard to the subject's gastric pH, the methodcomprising administering the ASD or pharmaceutical composition of thepresent disclosure to the subject. Some embodiments relate to a use of anilotinib ASD or pharmaceutical composition of the present disclosurefor delivering nilotinib to a subject without regard to the subject'sgastric pH, the use comprising administering the ASD or pharmaceuticalcomposition to the subject. Some embodiments relate to a nilotinib ASDor pharmaceutical composition of the present disclosure for use indelivering nilotinib to a subject without regard to the subject'sgastric pH, the use comprising administering the ASD or pharmaceuticalcomposition to the subject. Some embodiments relate to a use of anilotinib ASD or pharmaceutical composition of the present disclosure inthe manufacture of a medicament for delivering nilotinib to a subjectwithout regard to the subject's gastric pH, the delivery comprisingadministering the ASD or pharmaceutical composition to the subject.According to these embodiments, the subject may be administered thenilotinib ASD or pharmaceutical composition no matter whether thesubject has normal gastric pH or has elevated gastric pH as describedherein.

Pharmaceutical Composition Having Improved Variability

The pharmaceutical compositions of the present disclosure may, in someembodiments, provide a less variable in vivo pharmacokineticperformance.

As used herein, the phrase “improved variability composition” refers toa composition of the present disclosure that exhibits a lowercoefficient of variation with respect to one or more pharmacokineticparameters when administered to an appropriate set of healthy humansubjects, as compared to the coefficient of variation observed for aconventional immediate-release formulation of nilotinib (e.g., TASIGNA)when administered under similar conditions. For this assessment, the setof healthy human subjects should include a suitable number of subjectssuch that the study would be sufficiently powered to demonstratebioequivalence, according to standard practices and relevant FDAguidelines.

In some embodiments, the improved variability composition provides acoefficient of variation with respect to at least one pharmacokineticparameter that is 30% lower, 25% lower, 20% lower, 15% lower, 10% lower,or 5% lower than the coefficient of variation observed for the standardcommercial, immediate-release composition of nilotinib (e.g., TASIGNA)when administered under similar conditions. The pharmacokineticparameter can be any of C_(max), AUC_(last) and AUC_(0-inf). In someembodiments, the improved variability composition provides animprovement with respect to C_(max) and at least one of AUC_(last) andAUC_(0-inf). In other embodiments, the improved variability compositionprovides an improvement with respect to all of C_(max), AUC_(last) andAUC_(0-inf).

In particular, it has been observed that compositions according to thepresent disclosure can provide a lower coefficient of variation forpharmacokinetic parameters when administered to healthy human subjects.As shown in Example 6 (Table 27), test compositions administered in afasted state exhibited a lower coefficient of variation with respect toone or more of C_(max), AUC_(last) and AUC_(0-inf) as compared to thereference composition. For example, the observed CV for the testcompositions was at least 20% lower with respect to AUC_(0-inf), ascompared to the reference composition.

As shown in Example 7 (Table 31), test compositions administered in afed state exhibited a lower coefficient of variation with respect to oneor more of C_(max), AUC_(last) and AUC_(0-inf) as compared to thereference composition administered in a fasted state. For example, theobserved CV for the test composition (Regimen F) was at least 25% lowerwith respect to both C_(max) and AUC_(0-inf).

In some embodiments, the improved variability composition is an orallydisintegrating tablet as described herein.

Kits Comprising a Pharmaceutical Composition and a Package Insert

In some embodiments, the disclosure provides a kit containing apharmaceutical composition according to any of the above-describedaspects of the disclosure, as well as a package insert. As used herein,a “kit” is a commercial unit of sale, which may comprise a fixed numberof doses of the pharmaceutical composition. By way of example only, akit may provide a 30-day supply of dosage units of one or more fixedstrengths, the kit comprising 30 dosage units, 60 dosage units, 90dosage units, 120 dosage units, or other appropriate number according toa physician's instruction. As another example, a kit may provide a90-day supply of dosage units.

As used herein, “package insert” means a document which providesinformation on the use of the pharmaceutical composition, safetyinformation, and other information required by a regulatory agency. Apackage insert can be a physical printed document in some embodiments.Alternatively, a package insert can be made available electronically tothe user, such as via the Daily Med service of the National Library ofMedicines of the National Institute of Health, which provides up-to-dateprescribing information (seehttps://dailymed.nlm.nih.gov/dailymed/index.cfm).

In some embodiments, the pharmaceutical composition is an orallydisintegrating tablet as described herein. In the case of apharmaceutical composition in the form of an orally disintegratingtablet, the package insert will, at a minimum, instruct the user on theproper use instructions. The package insert will generally instruct theuser to place the tablet on the user's tongue and allow the tablet todisintegrate without chewing. The package insert will further includeadditional usage instructions, such as specific instructions pertainingto embodiments described below.

In some embodiments, the package insert informs a user of the kit thatthe pharmaceutical composition can be administered with food. In someembodiments, the package insert informs a user of the kit that thepharmaceutical composition can be administered with or without food. Insome embodiments, the package insert does not include a warning that thepharmaceutical composition should not be administered with food.

In some embodiments, the package insert informs a user of the kit thatthe pharmaceutical composition can be co-administered with a gastricacid-reducing agent. In some embodiments, the package insert does notcomprise a warning that the pharmaceutical composition should not beco-administered with H₂ antagonists or proton pump inhibitors.

In some embodiments, the package insert informs a user of the kit that aproton pump inhibitor can be co-administered with the pharmaceuticalcomposition. In some embodiments, the package insert does not include awarning that concomitant use of a proton pump inhibitor with thepharmaceutical composition should be avoided.

In some embodiments, the package insert informs a user of the kit thatan H₂ antagonist can be co-administered with the pharmaceuticalcomposition. In some embodiments, the package insert does not inform theuser to use an H₂ antagonist approximately 10 hours before orapproximately 2 hours after administration of the pharmaceuticalcomposition. In some embodiments, the package insert informs the userthat an H₂ antagonist can be used within approximately 10 hours beforeor within approximately 2 hours after administration of thepharmaceutical composition.

In some embodiments, the package insert informs a user of the kit thatan antacid can be co-administered with the pharmaceutical composition.In some embodiments, the package insert does not inform the user to usean antacid approximately 2 hours before or approximately 2 hours afteradministration of the pharmaceutical composition. In some embodiments,the package insert informs the user that an antacid can be used withinapproximately 2 hours before or within approximately 2 hours afteradministration of the pharmaceutical composition.

In some embodiments, the package insert informs a user of the kit thatthe pharmaceutical composition can be suitably administered to a userhaving chronically elevated gastric pH. In some embodiments, the packageinsert informs a user of the kit that the pharmaceutical composition canbe suitably administered to a patient diagnosed with or afflicted byachlorhydria or hypochlorhydria. In some embodiments, the package insertinforms a user of the kit that the pharmaceutical composition can besuitably administered to a patient diagnosed with or afflicted byHelicobacter pylori infection.

Embodiments of the Disclosure Include

Embodiment ASD1 is an amorphous solid dispersion comprising nilotiniband one or more polymers. Embodiment ASD2 is an amorphous soliddispersion comprising nilotinib and one or more polymers; wherein thenilotinib and the one or more polymers are present in the amorphoussolid dispersion in a w/w ratio of 20:80 to 95:5 (nilotinib:polymer).Embodiment ASD3 is an amorphous solid dispersion comprising nilotiniband one or more polymers, wherein the nilotinib and the one or morepolymers are present in the amorphous solid dispersion in a w/w ratio of40:60 to 70:30 (nilotinib:polymer). Embodiment ASD4 is an amorphoussolid dispersion comprising nilotinib and one or more polymers, whereinthe nilotinib and the one or more polymers are present in the amorphoussolid dispersion in a w/w ratio of 50:50 (nilotinib:polymer).

Embodiment ASD5 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD4, wherein the one or more polymers exhibitspH-dependent solubility. Embodiment ASD6 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD5, wherein the oneor more polymers comprises a hydroxypropyl methylcellulose acetatesuccinate. Embodiment ASD7 is the amorphous solid dispersion accordingto Embodiment ASD6, wherein the one or more polymers consistsessentially of a hydroxypropyl methylcellulose acetate succinate.Embodiment ASD8 is the amorphous solid dispersion according to any ofEmbodiments ASD6 to ASD7, wherein the one or more polymers comprise ahydroxypropyl methylcellulose acetate succinate characterized by anacetyl substitution of 7 to 11% and a succinyl substitution of 10 to14%.

Embodiment ASD9 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD5, wherein the one or more polymers comprises amethacrylic acid and ethyl acrylate copolymer. Embodiment ASD10 is theamorphous solid dispersion according to Embodiment ASD9, wherein the oneor more polymers consists essentially of a methacrylic acid and ethylacrylate copolymer. Embodiment ASD11 is the amorphous solid dispersionaccording to any of Embodiments ASD9 to ASD10, wherein the one or morepolymers comprise a methacrylic acid and ethyl acrylate copolymer thatis insoluble in an aqueous medium at pH of 5 or lower, and soluble in anaqueous medium at pH 5.5 or greater.

Embodiment ASD12 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD11 wherein the amorphous solid dispersionconsists essentially of nilotinib and the one or more polymers.

Embodiment ASD13 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD12, wherein the amorphous solid dispersioncomprises one or more antioxidants. Embodiment ASD14 is the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD13, whereinthe amorphous solid dispersion comprises one or more antioxidants thatare present in an amount of 0.001% to 2% by weight of the amorphoussolid dispersion. Embodiment ASD15 is the amorphous solid dispersionaccording to any of Embodiments ASD1 to ASD14, wherein the amorphoussolid dispersion comprises one or more antioxidants that are present inan amount of 0.05% to 0.5% by weight of the amorphous solid dispersion.Embodiment ASD16 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD15, wherein the amorphous solid dispersioncomprises one or more antioxidants selected from butylatedhydroxytoluene.

Embodiment ASD17 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD16, wherein the amorphous solid dispersion isprepared by a process comprising electrospraying. Embodiment ASD18 isthe amorphous solid dispersion according to any of Embodiments ASD1 toASD16, wherein the amorphous solid dispersion is an electrosprayedamorphous solid dispersion.

Embodiment ASD19 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD16, wherein the amorphous solid dispersion isprepared by a process comprising spray drying. Embodiment ASD20 is theamorphous solid dispersion according to any of Embodiments ASD1 toASD16, wherein the amorphous solid dispersion is a spray-dried amorphoussolid dispersion.

Embodiment ASD21 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD20, wherein the amorphous solid dispersionremains amorphous or essentially amorphous as determined by powder X-raydiffraction after storage at 40° C./75% relative humidity for 6 months.Embodiment ASD22 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD20, wherein the amorphous solid dispersionremains amorphous or essentially amorphous as determined by powder X-raydiffraction after storage at 25° C./60% relative humidity for 6 months.

Embodiment ASD23 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD20, wherein the amorphous solid dispersioncomprises a water content as measured by coulometric Karl Fischertitration of not more than 4% after storage at 25° C./60% RH for 12months. Embodiment ASD24 is the amorphous solid dispersion according toany of Embodiments ASD1 to ASD20, wherein the amorphous solid dispersioncomprises a water content as measured by coulometric Karl Fischertitration of not more than 4% after storage at 40° C./75% RH for 6months.

Embodiment ASD25 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD20, wherein the amorphous solid dispersion ischaracterized by an assay level of at least 90% as measured by highperformance liquid chromatography (HPLC) after storage at 25° C./60%relative humidity for 12 months. Embodiment ASD26 is the amorphous soliddispersion according to any of Embodiments ASD1 to ASD20, wherein theassay level of the amorphous solid dispersion is at least 90% afterstorage at 40° C./75% relative humidity for 6 months.

Embodiment ASD27 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD20, wherein the amorphous solid dispersioncomprises a total related substances as measured by HPLC of not morethan 1% after storage at 25° C./60% RH for 12 months. Embodiment ASD28is the amorphous solid dispersion according to any of Embodiments ASD1to ASD20, wherein the amorphous solid dispersion comprises a totalrelated substances as measured by HPLC of not more than 1% after storageat 40° C./75% RH for 6 months.

Embodiment ASD29 is the amorphous solid dispersion according to any ofEmbodiments ASD1 to ASD20, wherein the amorphous solid dispersioncomprises a glass transition temperature as measured by modulateddifferential scanning calorimetry that does not change by more than 5°C. after storage at 25° C./60% RH for 12 months. Embodiment ASD30 is theamorphous solid dispersion according to any of Embodiments ASD1 toASD20, wherein the amorphous solid dispersion comprises a glasstransition temperature as measured by modulated differential scanningcalorimetry that does not change by more than 5° C. after storage at 40°C./75% RH for 6 months.

ASD31 is the amorphous solid dispersion according to any of EmbodimentsASD1 to ASD30, wherein the nilotinib is nilotinib free base.

Embodiment PC1 is a pharmaceutical composition comprising the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD31.

Embodiment PC2 is a pharmaceutical composition comprising the amorphoussolid dispersion according to any of Embodiments ASD1 to ASD31, and oneor more pharmaceutically acceptable additives. Embodiment PC3 is thepharmaceutical composition of Embodiment PC2, wherein the one or morepharmaceutically acceptable additives comprises one or moresolubilizers, one or more buffering agent, one or more pH-adjustingagents, one or more surfactants, one or more antioxidants, one or morecarriers, or a combination thereof. Embodiment PC4 is the pharmaceuticalcomposition of Embodiment PC2, wherein the one or more pharmaceuticallyacceptable additives comprises one or more fillers, one or more binders,one or more lubricants, one or more disintegrants, one or more glidants,or a combination thereof. Embodiment PC5 is the pharmaceuticalcomposition of Embodiment PC4, wherein the pharmaceutical composition isa solid dosage form suitable for oral administration. Embodiment PC6 isthe pharmaceutical composition of Embodiment PC4, wherein thepharmaceutical composition is presented as a solid dosage form suitablefor oral administration, and comprising 25 to 100 mg nilotinib.

Embodiment PC7 is the pharmaceutical composition of Embodiment PC6,wherein, when the oral dosage form is administered to a healthy humansubjects in a fasted state, achieves an AUC_(0-inf) and C_(max) withinthe 80% to 125% bioequivalence criteria as compared to AUC_(0-inf) andC_(max) achieved upon administration of a reference composition, whereinthe reference composition is a conventional immediate-release nilotinibcomposition comprising 200 mg nilotinib monohydrochloride monohydrate.

Embodiment PC8 is the pharmaceutical composition of Embodiment PC6,wherein the pharmaceutical composition is effectively bioequivalentunder fasting conditions to a reference composition which is aconventional immediate-release nilotinib composition comprising 200 mgnilotinib monohydrochloride monohydrate; where effective bioequivalenceis established by: (a) a 90% confidence interval for AUC which isbetween 80% and 125%; and (b) a 90% confidence interval for C_(max),which is between 80% and 125%.

Embodiment PC9 is the pharmaceutical composition of Embodiment PC1 toPC8, wherein the pharmaceutical composition is a food-insensitivecomposition.

Embodiment PC10 is the pharmaceutical composition of Embodiment PC1 toPC9, wherein the pharmaceutical composition is a gastricacid-insensitive composition.

Embodiment PC11 is the pharmaceutical composition of Embodiment PC1 toPC10, wherein the pharmaceutical composition is an improved variabilitycomposition.

Embodiment ODT1 is a pharmaceutical composition in the form of an orallydisintegrating tablet and comprising an amorphous solid dispersionaccording to any of Embodiments ASD1 to ASD31; wherein the orallydisintegrating tablet is characterized by a disintegration time of 40seconds or less, as determined according to USP <701> Disintegration,using a basket-rack apparatus with disks in a medium of distilled water.

Embodiment ODT2 is the pharmaceutical composition of Embodiment ODT1,wherein the disintegration time is 35 seconds or less. Embodiment ODT3is the pharmaceutical composition of Embodiment ODT1, wherein thedisintegration time is 30 seconds or less. Embodiment ODT4 is thepharmaceutical composition of Embodiment ODT1, wherein thedisintegration time is 25 seconds or less. Embodiment ODT5 is thepharmaceutical composition of Embodiment ODT1, wherein thedisintegration time is 20 seconds or less.

Embodiment ODT6 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT5, characterized in that when the orallydisintegrating tablet is subjected to dissolution testing according toUSP <711> Dissolution using Apparatus 2 at 100 rpm and a dissolutionmedium consisting of 20 mM maleate buffer at pH 3, at least 10% of thenilotinib is released into the dissolution medium within 30 minutes.

Embodiment ODT7 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT5, characterized in that when the orallydisintegrating tablet is subjected to dissolution testing according toUSP <711> Dissolution using Apparatus 2 at 100 rpm and a dissolutionmedium consisting of 20 mM citrate buffer at pH 3.1, at least 10% of thenilotinib is released into the dissolution medium within 30 minutes.

Embodiment ODT8 is the pharmaceutical composition according to any ofEmbodiments ODT6 or ODT7, wherein at least 20% of the nilotinib isreleased into the dissolution medium within 30 minutes. Embodiment ODT9is the pharmaceutical composition according to any of Embodiments ODT6or ODT7, wherein at least 25% of the nilotinib is released into thedissolution medium within 30 minutes.

Embodiment ODT10 is the pharmaceutical composition according to any ofEmbodiments ODT6 or ODT7, wherein at least 30% of the nilotinib isreleased into the dissolution medium within 30 minutes. Embodiment ODT11is the pharmaceutical composition according to any of Embodiments ODT6or ODT7, wherein at least 35% of the nilotinib is released into thedissolution medium within 30 minutes. Embodiment ODT12 is thepharmaceutical composition according to any of Embodiments ODT6 or ODT7,wherein at least 40% of the nilotinib is released into the dissolutionmedium within 30 minutes. Embodiment ODT13 is the pharmaceuticalcomposition according to any of Embodiments ODT6 or ODT7, wherein atleast 45% of the nilotinib is released into the dissolution mediumwithin 30 minutes. Embodiment ODT14 is the pharmaceutical compositionaccording to any of Embodiments ODT6 or ODT7, wherein at least 50% ofthe nilotinib is released into the dissolution medium within 30 minutes.Embodiment ODT15 is the pharmaceutical composition according to any ofEmbodiments ODT6 or ODT7, wherein at least 55% of the nilotinib isreleased into the dissolution medium within 30 minutes. Embodiment ODT16is the pharmaceutical composition according to any of Embodiments ODT6or ODT7, wherein at least 60% of the nilotinib is released into thedissolution medium within 30 minutes.

Embodiment ODT17 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT16, wherein the orally disintegrating tablet ischaracterized by a breaking force of 1 kp to 18 kp, as determinedaccording to USP <1217> Tablet Breaking Force. Embodiment ODT18 is thepharmaceutical composition according to Embodiment ODT16, wherein thebreaking force is 2 kp to 12 kp. Embodiment ODT19 is the pharmaceuticalcomposition according to Embodiment ODT16, wherein the breaking force is2 kp to 8 kp. Embodiment ODT20 is the pharmaceutical compositionaccording to Embodiment ODT16, wherein the breaking force is 5 kp to 12kp. Embodiment ODT21 is the pharmaceutical composition according toEmbodiment ODT16, wherein the breaking force is 6 kp to 10 kp.

Embodiment ODT22 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT21, wherein the orally disintegrating tablet ischaracterized by a maximum mean weight loss of not more than 1.5%, asdetermined according to USP <1216> Tablet Friability. Embodiment ODT23is the pharmaceutical composition according to Embodiment ODT22, whereinthe maximum mean weight loss is not more than 1.0%. Embodiment ODT24 isthe pharmaceutical composition according to Embodiment ODT22, whereinthe maximum mean weight loss is not more than 0.75%. Embodiment ODT25 isthe pharmaceutical composition according to Embodiment ODT22, whereinthe maximum mean weight loss is not more than 0.5%.

Embodiment ODT26 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT25, wherein the orally disintegrating tabletcomprises: a) 10% to 75% of the amorphous solid dispersion, by weight ofthe tablet; b) 20% to 75% of one or more fillers, by weight of thetablet; and c) 5% to 15% of one or more disintegrants, by weight of thetablet. Embodiment ODT27 is the pharmaceutical composition according toEmbodiment ODT26, wherein the one or more fillers comprises at least oneof mannitol and microcrystalline cellulose. Embodiment ODT28 is thepharmaceutical composition according to Embodiment ODT26, wherein theone or more fillers comprises a combination of mannitol andmicrocrystalline cellulose. Embodiment ODT29 is the pharmaceuticalcomposition according to any of Embodiments ODT26 to ODT28, wherein theone or more disintegrants comprises at least one of crospovidone andcroscarmellose sodium. Embodiment ODT30 is the pharmaceuticalcomposition according to any of Embodiments ODT26 to ODT28, wherein theone or more disintegrants comprises a combination of crospovidone andcroscarmellose sodium.

Embodiment ODT31 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT25, wherein the orally disintegrating tabletcomprises granules, the granules comprising: a) 20% to 80% amorphoussolid dispersion, by weight of the granule; b) 15% to 60% of one or moregranulation fillers, by weight of the granule; and c) 2% to 20% of oneor more granulation disintegrants, by weight of the granule. EmbodimentODT32 is the pharmaceutical composition according to Embodiment ODT31,wherein the one or more granulation fillers comprises mannitol.Embodiment ODT33 is the pharmaceutical composition according toEmbodiment ODT31 or ODT32, wherein the one or more granulationdisintegrants comprises croscarmellose sodium.

Embodiment ODT34 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT25, wherein the orally disintegrating tabletcomprises granules, the granules comprising: a) 20% to 60% amorphoussolid dispersion, by weight of the granule; b) 40% to 80% of one or moregranulation fillers, by weight of the granule; and c) 2% to 10% of oneor more granulation disintegrants, by weight of the granule. EmbodimentODT35 is the pharmaceutical composition according to Embodiment ODT34,wherein the one or more granulation fillers comprises co-processedmannitol starch. Embodiment ODT36 is the pharmaceutical compositionaccording to Embodiment ODT34, wherein the one or more granulationfillers comprises microcrystalline cellulose. Embodiment ODT37 is thepharmaceutical composition according to Embodiment ODT34, wherein theone or more granulation fillers comprises a combination of co-processedmannitol starch and microcrystalline cellulose. Embodiment ODT38 is thepharmaceutical composition according to any of Embodiments ODT34 toODT37, wherein the one or more granulation disintegrants comprisescrospovidone.

Embodiment ODT39 is the pharmaceutical composition according to any ofEmbodiments ODT31 to ODT38, wherein 20% or less of the granules, byweight, are larger than 30 mesh. Embodiment ODT40 is the pharmaceuticalcomposition according to any of Embodiments ODT31 to ODT38, wherein 15%or less of the granules, by weight, are larger than 30 mesh.

Embodiment ODT41 is the pharmaceutical composition according to any ofEmbodiments ODT31 to ODT40, wherein the orally disintegrating tabletfurther comprises extra-granular excipients. Embodiment ODT42 is thepharmaceutical composition according to Embodiment ODT41, wherein theorally disintegrating tablet comprises: a) 20% to 80% of the granules,by weight of the tablet; and b) 20% to 80% of the extra-granularexcipients, by weight of the tablet. Embodiment ODT43 is thepharmaceutical composition according to any of Embodiments ODT41 toODT42, wherein the extra-granular excipients comprise: a) one or moretablet fillers; and b) one or more tablet disintegrants.

Embodiment ODT44 is the pharmaceutical composition according toEmbodiment ODT43, wherein the one or more tablet fillers comprisesmannitol. Embodiment ODT45 is the pharmaceutical composition accordingto Embodiment ODT43, wherein the one or more tablet fillers comprise acombination of mannitol and microcrystalline cellulose. Embodiment ODT46is the pharmaceutical composition according to any of Embodiments ODT43to ODT45, wherein the one or more tablet disintegrants comprises acombination of crospovidone and croscarmellose sodium. Embodiment ODT47is the pharmaceutical composition according to any of Embodiments ODT43to ODT45, wherein the one or more tablet disintegrants comprises acombination of crospovidone and croscarmellose sodium in a 1:1 (w/w)ratio.

Embodiment ODT48 is the pharmaceutical composition according toEmbodiment ODT41, wherein the orally disintegrating tablet comprises: a)80% to 99.5% of the granules, by weight of the tablet; and b) 0.5% to20% of the extra-granular excipients, by weight of the tablet.Embodiment ODT49 is the pharmaceutical composition according toEmbodiment ODT48, wherein the extra-granular excipients comprise one ormore tablet disintegrants. Embodiment ODT50 is the pharmaceuticalcomposition according to Embodiment ODT49, wherein the tabletdisintegrant comprises crospovidone. Embodiment ODT51 is thepharmaceutical composition according to Embodiment ODT49, wherein thegranules comprise a granulation disintegrant including crospovidone, andthe tablet disintegrant comprises crospovidone.

Embodiment ODT52 is the pharmaceutical composition according to any ofEmbodiments ODT31 to ODT38, wherein the orally disintegrating tabletdoes not comprise extra-granular excipients.

Embodiment ODT53 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT25, comprising granules and extra-granularexcipients, wherein: the granules comprise, by weight of the granule:(a) 40% to 80% of the amorphous solid dispersion consisting essentiallyof: nilotinib free base and hydroxypropyl methylcellulose acetatesuccinate in a w/w ratio (nilotinib:polymer) of 50:50; and 0.05% to 0.5%of butylated hydroxytoluene, by weight of the amorphous soliddispersion; (b) 15% to 60% of one or more granulation fillers includingmannitol; and (c) 2% to 20% of one or more granulation disintegrantsincluding croscarmellose sodium; the extra-granular excipients comprise,by weight of the tablet: (a) 30% to 50% of one or more tablet fillersincluding at least one of mannitol and microcrystalline cellulose; and(b) 5% to 20% of one or more tablet disintegrants including at least oneof crospovidone and croscarmellose sodium; wherein the tablet comprises30% to 70% granules, by weight of the tablet.

Embodiment ODT54 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT25, comprising granules and extra-granularexcipients, wherein: the granules comprise, by weight of the granule:(a) 20% to 60% of the amorphous solid dispersion consisting essentiallyof: nilotinib free base and hydroxypropyl methylcellulose acetatesuccinate in a w/w ratio (nilotinib:polymer) of 50:50; and 0.05% to 1%of butylated hydroxytoluene, by weight of the amorphous soliddispersion; (b) 40% to 80% of one or more granulation fillers includingco-processed mannitol starch, microcrystalline cellulose, or acombination thereof; and (c) 2% to 10% of one or more granulationdisintegrants including crospovidone; the extra-granular excipientscomprise one or more tablet disintegrants including crospovidone;wherein the tablet comprises 80% to 99.5% granules, by weight of thetablet.

Embodiment ODT55 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT25, wherein the orally disintegrating tabletsubstantially conforms to the formulation provided in Table 36.

Embodiment ODT56 is the pharmaceutical composition of any of EmbodimentsODT1 to ODT55, wherein the orally disintegrating tablet comprises 15% to60% of the amorphous solid dispersion, by weight of the tablet.Embodiment ODT57 is the pharmaceutical composition of any of EmbodimentsODT1 to ODT55, wherein the orally disintegrating tablet comprises 20% to50% of the amorphous solid dispersion, by weight of the tablet.Embodiment ODT58 is the pharmaceutical composition of any of EmbodimentsODT1 to ODT55, wherein the orally disintegrating tablet comprises 25% to40% of the amorphous solid dispersion, by weight of the tablet.Embodiment ODT59 is the pharmaceutical composition of any of EmbodimentsODT1 to ODT55, wherein the orally disintegrating tablet comprises 30% ofthe amorphous solid dispersion, by weight of the tablet.

Embodiment ODT60 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT59, wherein the orally disintegrating tabletfurther comprises one or more lubricants. Embodiment ODT61 is thepharmaceutical composition according to Embodiment ODT60, wherein thelubricant comprises magnesium stearate.

Embodiment ODT62 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT59, wherein the orally disintegrating tabletfurther comprises one or more glidants. Embodiment ODT63 is thepharmaceutical composition according to Embodiment ODT62, wherein theglidant comprises colloidal silica. Embodiment ODT64 is thepharmaceutical composition according to Embodiment ODT62, wherein theglidant comprises hydrophobic colloidal silica. Embodiment ODT65 is thepharmaceutical composition according to Embodiment ODT62, wherein theglidant comprises hydrophilic colloidal silica.

Embodiment ODT66 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT65, wherein the orally disintegrating tablet isfree from flavorants. Embodiment ODT67 is the pharmaceutical compositionaccording to any of Embodiments ODT1 to ODT65, wherein the orallydisintegrating tablet comprises one or more flavorants. Embodiment ODT68is the pharmaceutical composition according to any of Embodiments ODT1to ODT67, wherein the orally disintegrating tablet is free fromtaste-masking agents. Embodiment ODT69 is the pharmaceutical compositionaccording to any of Embodiments ODT1 to ODT68, wherein the orallydisintegrating tablet does not include effervescent agents.

Embodiment ODT70 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT69, wherein the orally disintegrating tablet isindividually sealed within packaging material adapted to protect theorally disintegrating tablet from external moisture. Embodiment ODT71 isthe pharmaceutical composition according to any of Embodiments ODT1 toODT70, wherein the orally disintegrating tablet is individually sealedwithin a pouch. Embodiment ODT72 is the pharmaceutical compositionaccording to any of Embodiments ODT1 to ODT70, wherein the orallydisintegrating tablet is individually sealed within a blister pack.

Embodiment ODT73 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT72, wherein the orally disintegrating tabletcomprises 10 mg to 100 mg nilotinib. Embodiment ODT74 is thepharmaceutical composition according to any of Embodiments ODT1 toODT72, wherein the orally disintegrating tablet comprises 15 mg to 75 mgnilotinib.

Embodiment ODT75 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT74, wherein, when the orally disintegratingtablet is administered to a healthy human subjects in a fasted state,achieves an AUC_(0-inf) and C_(max) within the 80% to 125%bioequivalence criteria as compared to AUC_(0-inf) and C_(max) achievedupon administration of a reference composition, wherein the referencecomposition is a conventional immediate-release nilotinib compositioncomprising 200 mg nilotinib monohydrochloride monohydrate.

Embodiment ODT76 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT75, wherein the orally disintegrating tablet iseffectively bioequivalent under fasting conditions to a referencecomposition which is a conventional immediate-release nilotinibcomposition comprising 200 mg nilotinib monohydrochloride monohydrate;where effective bioequivalence is established by: (a) a 90% confidenceinterval for AUC which is between 80% and 125%; and (b) a 90% confidenceinterval for C_(max), which is between 80% and 125%.

Embodiment ODT77 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT76, wherein the pharmaceutical composition is afood-insensitive composition.

Embodiment ODT78 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT77, wherein the pharmaceutical composition is agastric acid-insensitive composition.

Embodiment ODT79 is the pharmaceutical composition according to any ofEmbodiments ODT1 to ODT78, wherein the pharmaceutical composition is animproved variability composition.

Embodiment MT1 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC11 or ODT1 to ODT79.

Embodiment MT2 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC11 or ODT1 to ODT79, wherein the pharmaceutical composition isadministered without regard to consumption of food. Embodiment MT3 is amethod of treating a proliferative disorder in a patient in needthereof, the method comprising administering to the patient apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79, wherein the pharmaceutical composition is administeredwithout regard to whether the patient is in a fasted state or a fedstate. Embodiment MT4 is a method of treating a proliferative disorderin a patient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC11 or ODT1 to ODT79, without a food effect.

Embodiment MT5 is a method of safely delivering nilotinib to a patientin need thereof, the method comprising: (a) administering to the patienta therapeutically effective amount of a pharmaceutical compositionaccording to any of Embodiments PC1 to PC11 or ODT1 to ODT79, and (b)administering a meal to the patient; wherein steps (a) and (b) occurwithin less than two hours of each other.

Embodiment MT6 is a method of delivering a therapeutically effectiveamount of nilotinib to a patient without regard to consumption of food,comprising administering to the patient a pharmaceutical compositionaccording to any of Embodiments PC1 to PC11 or ODT1 to ODT79. EmbodimentMT7 is a method of delivering a therapeutically effective amount ofnilotinib to a patient without regard to whether the patient is in afasted state or a fed state, comprising administering to the patient apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79.

Embodiment MT8 is the method according to any of Embodiments MT1 to MT7,wherein administration of the pharmaceutical composition to the patientin a fed state results in plasma C_(max) of nilotinib that is less thanthe plasma C_(max) of nilotinib resulting from administration of thepharmaceutical composition to the patient in a fasted state. EmbodimentMT9 is the method according to any of Embodiments MT1 to MT7, whereinadministration of the pharmaceutical composition to the patient in a fedstate results in plasma C_(max) of nilotinib that is within 30% of theplasma C_(max) of nilotinib resulting from administration of thepharmaceutical composition to the patient in a fasted state.

Embodiment MT10 is the method according to any of Embodiments MT1 toMT9, wherein administration of the pharmaceutical composition to thepatient in a fed state results in plasma AUC of nilotinib that is lessthan the plasma AUC of nilotinib resulting from administration of thepharmaceutical composition to the patient in a fasted state. EmbodimentMT11 is the method according to any of Embodiments MT1 to MT9, whereinadministration of the pharmaceutical composition to the patient in a fedstate results in plasma AUC of nilotinib that is within 30% of theplasma AUC of nilotinib resulting from administration of thepharmaceutical composition to the patient in a fasted state. EmbodimentMT12 is the method according to any of Embodiments MT1 to MT9, whereinadministration of the pharmaceutical composition to the patient in a fedstate results in plasma AUC of nilotinib that is within 15% of theplasma AUC of nilotinib resulting from administration of thepharmaceutical composition to the patient in a fasted state. EmbodimentMT13 is the method according to any of Embodiments MT10 to MT12, whereinAUC is AUC_(0-12 h). Embodiment MT14 is the method according to any ofEmbodiments MT10 to MT12, wherein AUC is AUC_(0-24 h). Embodiment MT15is the method according to any of Embodiments MT10 to MT12, wherein AUCis AUC_(0-last). Embodiment MT16 is the method according to any ofEmbodiments MT10 to MT12, wherein AUC is AUC_(0-inf).

Embodiment MT17 is the method according to any of Embodiments MT1 toMT7, wherein administration of the pharmaceutical composition to thepatient in a fasted state results in plasma C_(max) of nilotinib that isgreater than the plasma C_(max) of nilotinib resulting fromadministration of an immediate-release crystalline nilotinib formulationthat has two times to four times the amount of nilotinib as thepharmaceutical composition. Embodiment MT18 is the method according toany of Embodiments MT1 to MT7, wherein administration of thepharmaceutical composition to the patient in a fed state results inplasma C_(max) of nilotinib that is within 25% of the plasma C_(max) ofnilotinib resulting from administration of an immediate-releasecrystalline nilotinib formulation that has two times to four times theamount of nilotinib as the pharmaceutical composition.

Embodiment MT19 is the method according to any of Embodiments MT1 toMT7, wherein administration of the pharmaceutical composition to thepatient in a fasted state results in plasma AUC of nilotinib that isgreater than the plasma AUC of nilotinib resulting from administrationof an immediate-release crystalline nilotinib formulation that has twotimes to four times the amount of nilotinib as the pharmaceuticalcomposition. Embodiment MT20 is the method according to any ofEmbodiments MT1 to MT7, wherein administration of the pharmaceuticalcomposition to the patient in a fed state results in plasma AUC ofnilotinib that is within 25% of the plasma AUC of nilotinib resultingfrom administration of an immediate-release crystalline nilotinibformulation that has two times to four times the amount of nilotinib asthe pharmaceutical composition. Embodiment MT21 is the method accordingto any of Embodiments MT1 to MT7, wherein administration of thepharmaceutical composition to the patient in a fed state results inplasma AUC of nilotinib that is within 20% of the plasma AUC ofnilotinib resulting from administration of an immediate-releasecrystalline nilotinib formulation that has two times to four times theamount of nilotinib as the pharmaceutical composition. Embodiment MT22is the method according to any of Embodiments MT19 to MT21, wherein AUCis AUC_(0-12 h). Embodiment MT23 is the method according to any ofEmbodiments MT19 to MT21, wherein AUC is AUC_(0-24 h). Embodiment MT24is the method according to any of Embodiments MT19 to MT21, wherein AUCis AUC_(0-last). Embodiment MT25 is the method according to any ofEmbodiments MT19 to MT21, wherein AUC is AUC_(0-inf).

Embodiment MT26 is a method of treating a proliferative disorder in apatient in need thereof, the method comprising administering to thepatient a pharmaceutical composition according to any of Embodiments PC1to PC11 or ODT1 to ODT79, without regard to whether the patient isco-administered a proton pump inhibitor. Embodiment MT27 is a method ofdelivering a therapeutically effective amount of nilotinib to a patientwho is co-administered a proton pump inhibitor, comprising administeringto the patient (a) a pharmaceutical composition according to any ofEmbodiments PC1 to PC11 or ODT1 to ODT79, and (b) a proton pumpinhibitor.

Embodiment MT28 is the method according to any of Embodiments MT1 toMT27, wherein the proliferative disorder is cancer. Embodiment MT29 isthe method according to any of Embodiments MT1 to MT27, wherein theproliferative disorder is Philadelphia chromosome positive chronicmyeloid leukemia. Embodiment MT30 is the method according to any ofEmbodiments MT1 to MT27, wherein the proliferative disorder is chronicphase Philadelphia chromosome positive chronic myeloid leukemiaresistant or intolerant to prior tyrosine kinase inhibitor therapy.

Embodiment MS1 is a method of delivering a therapeutically relevantexposure of nilotinib to a subject without regard to whether the subjectis in a fasted state or a fed state, the method comprising administeringto the subject a pharmaceutical composition according to any ofEmbodiments PC1 to PC11 or ODT1 to ODT79.

Embodiment MS2 is the method according to Embodiment MS1, whereinadministration of the pharmaceutical composition to the subject in a fedstate results in plasma C_(max) of nilotinib that is less than theplasma C_(max) of nilotinib resulting from administration of thepharmaceutical composition to the subject in a fasted state. EmbodimentMS3 is the method according to Embodiment MS1, wherein administration ofthe pharmaceutical composition to the subject in a fed state results inplasma C_(max) of nilotinib that is within 30% of the plasma C_(max) ofnilotinib resulting from administration of the pharmaceuticalcomposition to the subject in a fasted state.

Embodiment MS4 is the method according to Embodiment MS1, whereinadministration of the pharmaceutical composition to the subject in a fedstate results in plasma AUC of nilotinib that is less than the plasmaAUC of nilotinib resulting from administration of the pharmaceuticalcomposition to the subject in a fasted state. Embodiment MS5 is themethod according to Embodiment MS1, wherein administration of thepharmaceutical composition to the subject in a fed state results inplasma AUC of nilotinib that is within 30% of the plasma AUC ofnilotinib resulting from administration of the pharmaceuticalcomposition to the subject in a fasted state. Embodiment MS6 is themethod according to Embodiment MS1, wherein administration of thepharmaceutical composition to the subject in a fed state results inplasma AUC of nilotinib that is within 15% of the plasma AUC ofnilotinib resulting from administration of the pharmaceuticalcomposition to the subject in a fasted state. Embodiment MS7 is themethod according to any of Embodiments MS4 to MS6, wherein AUC isAUC_(0-12 h). Embodiment MS8 is the method according to any ofEmbodiments MS4 to MS6, wherein AUC is AUC_(0-24 h). Embodiment MS9 isthe method according to any of Embodiments MS4 to MS6, wherein AUC isAUC_(0-last). Embodiment MS10 is the method according to any ofEmbodiments MS4 to MS6, wherein AUC is AUC_(0-inf).

Embodiment MS11 is the method according to Embodiment MS1, whereinadministration of the pharmaceutical composition to the subject in afasted state results in plasma C_(max) of nilotinib that is greater thanthe plasma C_(max) of nilotinib resulting from administration of animmediate-release crystalline nilotinib formulation that has two timesto four times the amount of nilotinib as the pharmaceutical composition.Embodiment MS12 is the method according to Embodiment MS1, whereinadministration of the pharmaceutical composition to the subject in a fedstate results in plasma C_(max) of nilotinib that is within 25% of theplasma C_(max) of nilotinib resulting from administration in a fastedstate of an immediate-release crystalline nilotinib formulation that hastwo times to four times the amount of nilotinib as the pharmaceuticalcomposition.

Embodiment MS13 is the method according to Embodiment MS1, whereinadministration of the pharmaceutical composition to the subject in afasted state results in plasma AUC of nilotinib that is greater than theplasma AUC of nilotinib resulting from administration of animmediate-release crystalline nilotinib formulation that has two timesto four times the amount of nilotinib as the pharmaceutical composition.Embodiment MS14 is the method according to Embodiment MS1, whereinadministration of the pharmaceutical composition to the subject in a fedstate results in plasma AUC of nilotinib that is within 25% of theplasma AUC of nilotinib resulting from administration in a fasted stateof an immediate-release crystalline nilotinib formulation that has twotimes to four times the amount of nilotinib as the pharmaceuticalcomposition. Embodiment MS15 is the method according to Embodiment MS1,wherein administration of the pharmaceutical composition to the subjectin a fed state results in plasma AUC of nilotinib that is within 20% ofthe plasma AUC of nilotinib resulting from administration in a fastedstate of an immediate-release crystalline nilotinib formulation that hastwo times to four times the amount of nilotinib as the pharmaceuticalcomposition. Embodiment MS16 is the method according to any ofEmbodiments MS13 to MS15, wherein AUC is AUC_(0-12 h). Embodiment MS17is the method according to any of Embodiments MS13 to MS15, wherein AUCis AUC_(0-24 h). Embodiment MS18 is the method according to any ofEmbodiments MS13 to MS15, wherein AUC is AUC_(0-last). Embodiment MS19is the method according to any of Embodiments MS13 to MS15, wherein AUCis AUC_(0-inf).

Embodiment TR1 is a treatment regimen for treating a proliferativedisorder in a patient in need thereof, the regimen comprising: (a)administering to the patient a first dose, the first dose comprising aproton pump inhibitor; and (b) within 12 hours of the first dose,administering a second dose to the patient, the second dose comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79.

Embodiment TR2 is a treatment regimen for treating a proliferativedisorder and a condition caused by the overproduction of stomach acid orexacerbated by stomach acid in a patient in need thereof, the regimencomprising: (a) administering to the patient a first dose, the firstdose comprising therapeutically effective amount of a proton pumpinhibitor; and (b) within 12 hours of the first dose, administering asecond dose to the patient, the second dose comprising a pharmaceuticalcomposition according to any of Embodiments PC1 to PC11 or ODT1 toODT79.

Embodiment TR3 is the treatment regimen according to any of EmbodimentsTR1 to TR2, wherein the first dose comprises a standard dosage of aproton pump inhibitor selected from rabeprazole, esomeprazole,lansoprazole, omeprazole, pantoprazole, dexlansoprazole, or acombination thereof. Embodiment TR4 is the treatment regimen accordingto any of Embodiments TR1 to TR2, wherein the first dose comprises astandard dosage of omeprazole.

Embodiment TR5 is the treatment regimen according to any of EmbodimentsTR1 to TR4, wherein step (a) occurs before step (b). Embodiment TR6 isthe treatment regimen according to any of Embodiments TR1 to TR4,wherein step (b) occurs before step (a). Embodiment TR7 is the treatmentregimen according to any of Embodiments TR1 to TR6, wherein the seconddose is administered within 8 hours of the first dose. Embodiment TR8 isthe treatment regimen according to any of Embodiments TR1 to TR6,wherein the second dose is administered within 6 hours of the firstdose. Embodiment TR9 is the treatment regimen according to any ofEmbodiments TR1 to TR6, wherein the second dose is administered within 4hours of the first dose. Embodiment TR10 is the treatment regimenaccording to any of Embodiments TR1 to TR6, wherein the second dose isadministered within 2 hours of the first dose. Embodiment TR11 is thetreatment regimen according to any of Embodiments TR1 to TR6, whereinthe first dose and the second dose are administered concurrently.

Embodiment TR12 is a treatment regimen for treating a proliferativedisorder in a patient in need thereof, the regimen comprising: (a)administering to the patient a first dose, the first dose comprising anH₂ antagonist; and (b) within 10 hours after the first dose,administering a second dose to the patient, the second dose comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79. Embodiment TR13 is a treatment regimen for treating aproliferative disorder and a condition caused by the overproduction ofstomach acid or exacerbated by stomach acid in a patient in needthereof, the regimen comprising: (a) administering to the patient afirst dose, the first dose comprising a therapeutically effective amountof an H₂ antagonist; and (b) within 10 hours after the first dose,administering a second dose to the patient, the second dose comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79. Embodiment TR14 is the treatment regimen according toany of Embodiments TR12 to TR13, wherein the second dose is administeredwithin 8 hours of the first dose. Embodiment TR15 is the treatmentregimen according to any of Embodiments TR12 to TR13, wherein the seconddose is administered within 6 hours of the first dose. Embodiment TR16is the treatment regimen according to any of Embodiments TR12 to TR13,wherein the second dose is administered within 4 hours of the firstdose. Embodiment TR17 is the treatment regimen according to any ofEmbodiments TR12 to TR13, wherein the second dose is administered within2 hours of the first dose. Embodiment TR18 is the treatment regimenaccording to any of Embodiments TR12 to TR13, wherein the first dose andthe second dose are administered concurrently.

Embodiment TR19 is a treatment regimen for treating a proliferativedisorder in a patient in need thereof, the regimen comprising: (a)administering to the patient a first dose, the first dose comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79; and (b) within 2 hours after the first dose,administering a second dose to the patient, the second dose comprisingan H₂ antagonist. Embodiment TR20 is a treatment regimen for treating aproliferative disorder and a condition caused by the overproduction ofstomach acid or exacerbated by stomach acid in a patient in needthereof, the regimen comprising: (a) administering to the patient afirst dose, the first dose comprising a pharmaceutical compositionaccording to any of Embodiments PC1 to PC11 or ODT1 to ODT79; and (b)within 2 hours after the first dose, administering a second dose to thepatient, the second dose comprising a therapeutically effective amountof an H₂ antagonist. Embodiment TR21 is the treatment regimen accordingto any of Embodiments TR19 to TR20, wherein the first dose and thesecond dose are administered concurrently. Embodiment TR22 is thetreatment regimen according to any of Embodiments TR12 to TR21, whereinthe H₂ antagonist is selected from famotidine, cimetidine, nizatidine,ranitidine, or a combination thereof. Embodiment TR23 is the treatmentregimen according to any of Embodiments TR12 to TR21, wherein the H₂antagonist is famotidine.

Embodiment TR24 is a treatment regimen for treating a proliferativedisorder in a patient in need thereof, the regimen comprising: (a)administering to the patient a first dose, the first dose comprising anantacid; and (b) within 2 hours of the first dose, administering asecond dose to the patient, the second dose comprising a pharmaceuticalcomposition according to any of Embodiments PC1 to PC11 or ODT1 toODT79. Embodiment TR25 is a treatment regimen for treating aproliferative disorder and a condition caused by the overproduction ofstomach acid or exacerbated by stomach acid in a patient in needthereof, the regimen comprising: (a) administering to the patient afirst dose, the first dose comprising a pharmaceutical compositionaccording to any of Embodiments PC1 to PC11 or ODT1 to ODT79; and (b)within 2 hours of the first dose, administering a second dose to thepatient, the second dose comprising a therapeutically effective amountof an antacid. Embodiment TR26 is the treatment regimen according to anyof Embodiments TR24 to TR25, wherein the first dose and the second doseare administered concurrently. Embodiment TR27 is the treatment regimenaccording to any of Embodiments TR24 to TR26, wherein the antacid isselected from aluminum hydroxide, magnesium hydroxide, and combinationsthereof.

Embodiment TR28 is the treatment regimen according to any of EmbodimentsTR1 to TR27, wherein the proliferative disorder is cancer. EmbodimentTR29 is the treatment regimen according to any of Embodiments TR1 toTR27, wherein the proliferative disorder is Philadelphia chromosomepositive chronic myeloid leukemia. Embodiment TR30 is the treatmentregimen according to any of Embodiments TR1 to TR27, wherein theproliferative disorder is chronic phase Philadelphia chromosome positivechronic myeloid leukemia resistant or intolerant to prior tyrosinekinase inhibitor therapy.

Embodiment TR31 is the treatment regimen according to any of EmbodimentsTR1 to TR30, wherein administration of the pharmaceutical compositionprovides a therapeutically relevant exposure of nilotinib to thepatient.

Embodiment KT1 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79 and a package insert, wherein the package insertinforms the user that the pharmaceutical composition can be administeredwith food. Embodiment KT2 is a kit for sale to a user, the kitcomprising a pharmaceutical composition according to any of EmbodimentsPC1 to PC11 or ODT1 to ODT79 and a package insert, wherein the packageinsert informs the user that the pharmaceutical composition can beadministered with or without food. Embodiment KT3 is a kit for sale to auser, the kit comprising a pharmaceutical composition according to anyof Embodiments PC1 to PC11 or ODT1 to ODT79 and a package insert,wherein the package insert does not include a warning that thepharmaceutical composition should not be administered with food.

Embodiment KT4 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79 and a package insert, wherein the package insert thatinforms the user that a proton pump inhibitor can be co-administeredwith the pharmaceutical composition. Embodiment KT5 is a kit for sale toa user, the kit comprising a pharmaceutical composition according to anyof Embodiments PC1 to PC11 or ODT1 to ODT79 and a package insert,wherein the package insert does not include a warning that concomitantuse of a proton pump inhibitor with the pharmaceutical compositionshould be avoided.

Embodiment KT6 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79 and a package insert, wherein the package insertinforms the user that an H₂ antagonist can be co-administered with thepharmaceutical composition. Embodiment KT7 is a kit for sale to a user,the kit comprising a pharmaceutical composition according to any ofEmbodiments PC1 to PC11 or ODT1 to ODT79 and a package insert, whereinthe package insert does not inform a user of the kit to use an H₂antagonist approximately 10 hours before or approximately 2 hours afteradministration of the pharmaceutical composition. Embodiment KT8 is akit for sale to a user, the kit comprising a pharmaceutical compositionaccording to any of Embodiments PC1 to PC11 or ODT1 to ODT79 and apackage insert, wherein the package insert informs a user of the kitthat an H₂ antagonist can be used within approximately 10 hours beforeor within approximately 2 hours after administration of thepharmaceutical composition.

Embodiment KT9 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79 and a package insert, wherein the package insertinforms the user that an antacid can be co-administered with thepharmaceutical composition. Embodiment KT10 is a kit for sale to a user,the kit comprising a pharmaceutical composition according to any ofEmbodiments PC1 to PC11 or ODT1 to ODT79 and a package insert, whereinthe package insert does not inform a user of the kit to use an antacidapproximately 2 hours before or approximately 2 hours afteradministration of the pharmaceutical composition. Embodiment KT11 is akit for sale to a user, the kit comprising a pharmaceutical compositionaccording to any of Embodiments PC1 to PC11 or ODT1 to ODT79 and apackage insert, wherein the package insert informs a user of the kitthat an antacid can be used within approximately 2 hours before orwithin approximately 2 hours after administration of the pharmaceuticalcomposition.

Embodiment KT12 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79 and a package insert, wherein the package insertinforms the user that the pharmaceutical composition can be suitablyadministered if the user has chronically elevated gastric pH. EmbodimentKT13 is a kit for sale to a user, the kit comprising a pharmaceuticalcomposition according to any of Embodiments PC1 to PC11 or ODT1 to ODT79and a package insert, wherein package insert informs the user that thepharmaceutical composition can be suitably administered if the user hasbeen diagnosed with or is afflicted by achlorhydria or hypochlorhydria.Embodiment KT14 is a kit for sale to a user, the kit comprising apharmaceutical composition according to any of Embodiments PC1 to PC11or ODT1 to ODT79 and a package insert, wherein the package insertinforms the user that the pharmaceutical composition can be suitablyadministered if the user has been diagnosed with or is afflicted byHelicobacter pylori infection.

The present disclosure will be further illustrated and/or demonstratedin the following Examples, which are given forillustration/demonstration purposes only and are not intended to limitthe disclosure in any way.

EXAMPLES

In addition to the Examples provided herein, the present disclosure isfurther supported by Examples disclosed in PCT/US 2021/15864 (filed Jan.29, 2021), which Examples and associated Figures are hereby incorporatedby reference in their entirety.

Example 1 Preparation of Nilotinib ASDs and Stability Study Under HarshConditions

Nilotinib ASDs were prepared according to embodiments of the presentdisclosure. A study was then performed to assess the chemical andphysical stability of the nilotinib ASDs under harsh acceleratedconditions.

Nilotinib ASDs were prepared with either EUDRAGIT L100-55 or HPMC-AS asthe polymer, in the ratios shown in Table 2. To prepare eachcomposition, appropriate quantities of the polymer and nilotinib weredissolved in a 50:50 (v/v) solvent mixture of tetrahydrofuran andmethanol to provide a liquid feedstock. (The tetrahydrofuran wasstabilized with a small quantity of BHT as an antioxidant; therefore,the ASDs prepared in this example will contain a small, unquantifiedamount of BHT along with nilotinib and polymer.)

TABLE 2 Composition of the Nilotinib ASDs for Example 1. Nilotinib:Polymer Components Ratio (w/w) Nilotinib:EUDRAGIT 50:50 L100-55 60:4070:30 80:20 Nilotinib:HPMC-AS 50:50 60:40 70:30 80:20

The resulting feedstocks were sprayed at a total solid concentration of20 mg/ml using the Nanocopoeia ES machine ENS-P. For each spray run, thespray process parameters, such as extractor voltage and flow rate, wereadjusted to achieve an acceptable spray plume.

Following the electrospray processing, each ASD (now in the form of apowder) was subjected to a secondary drying procedure to reduce thelevels of residual solvents and moisture. For secondary drying, the ASDpowders were placed in an appropriate container and placed into an oven(Lindberg Blue M, Model V01218A) which was heated to 80° C. The powderswere dried under vacuum (negative 20″ to 28″ Hg) for six hours.

For compositions that required multiple spray sub-batches in order toprovide enough ASD material to support the stability study, materialobtained from sub-batches was combined into a single blend using aResodyn LabRam II acoustic mixer. Sub-batches were placed into a singlecontainer and blended for 2 minutes at a force setting of 40 G.

The resulting ASDs were placed on stability in an open dish underaggressive conditions at 50° C./80% RH. The ASD powders were assessed att=0, 1 week, 2 weeks, and 4 weeks for amorphicity (XRD), water content(Karl Fisher), glass transition temperature (DSC), and assay/relatedsubstances (HPLC).

Amorphicity

Amorphicity (i.e., the lack of crystallinity) for the ASDs was assessedby XRD. Diffraction patterns were obtained by x-ray diffraction using aRigaku MiniFlex 600. The X-ray source was a long anode Cu Kα. Sampleswere prepared by placing a small amount of ASD powder on a Rigakuzero-background sample holder with a 0.1 mm indent. A glass slide wasthen used to firmly pack the powder and ensure the surface of the samplewas level with the edge of the sample holder. Instrument details andmeasurement conditions are specified in Table 3.

TABLE 3 Rigaku MiniFlex instrument and measurement conditions. ParameterCondition Spin On Slit condition Variable and fixed slit system OpticalSoller (inc.): 5.0° IHS: 10.0 mm DS: 1.250° SS: 8.0 mm device Soller(rec.): 5.0° IHS: 13.0 mm Monochromatization: Kb filter (X2, 0.03 mm)Detector D/tex Measurement Scan axis: Mode: continuous Start: 5.0° Stop:40° condition theta/2-theta Step: 0.02° Speed: 5.0°/min Voltage: 40 kVCurrent: 15 mA

The ASDs were evaluated for amorphicity post-spray (t=0) and afterstability. Each XRD scan was assessed for the presence of crystallinepeaks, with the results listed in Table 4.

TABLE 4 Summary of ASD amorphicity data for ASDs of Example 1. TimeNilotinib:EUDRAGIT L100-55 Nilotinib:HPMC-AS Point 50:50 60:40 70:3080:20 50:50 60:40 70:30 80:20 0 Amorphous Amorphous Amorphous AmorphousAmorphous Amorphous Amorphous Amorphous 1 week Amorphous AmorphousCrystalline Crystalline Amorphous Amorphous Amorphous Crystalline 2weeks Amorphous Amorphous Crystalline Crystalline Amorphous CrystallineCrystalline Crystalline 4 weeks Amorphous Amorphous CrystallineCrystalline Amorphous Crystalline Crystalline Crystalline

As shown in Table 4, each ASD was amorphous post-electrosprayprocessing. After one week on stability at 50° C./80% RH, the ASDs witha lower drug load (Nilotinib:EUDRAGIT L100-55 at 50:50 and 60:40;Nilotinib:HPMC-AS at 50:50, 60:40 and 70:30) remained amorphous;however, the ASDs with a higher drug load had begun to show signs ofcrystallization in the XRD scans. Only the ASD formulations with thelowest drug loads (Nilotinib:EUDRAGIT L100-55 at 50:50 and 60:40;Nilotinib:HPMC-AS at 50:50) were amorphous at week 2, and remainedamorphous throughout the entire four-week study; all other ASDs showedthe presence of crystalline peaks by week 2. Despite the fact thatcrystallinity was observed after some time for many of these ASDs, thisresult was considered promising because of the harsh accelerated storageconditions (which are not reflective of real-world storage conditions).

Water Content

Water content was determined by Karl Fischer coulometric titrationmethod, using a Mettler Toledo C30S Karl Fischer with Stromboli OvenSampler. Approximately 40-50 mg of ASD powder was weighed into a glassStromboli sample vial and vial was immediately sealed. The vial was thenplaced onto instrument and analysis was conducted using nitrogen carriergas. Instrument details and measurement conditions are specified inTable 5.

TABLE 5 Karl Fisher instrument and measurement conditions. ParameterCondition Drift duration 3 min Drift wait time 60 sec Maximum driftallowance 25 μg/min Oven temperature 110° C. Mix time 60 sec Stir speed50%

The initial moisture levels were very consistent for all eight ASDs, asshown in Table 6. Likewise, all ASDs demonstrated a rapid increase inwater content after exposure for one week to high humidity, whichleveled off and remained fairly constant (3.5%-5%) for the remainder ofthe study. Despite some variability in the data, the ASDs comprisingeither EUDRAGIT L100-55 or HPMC-AS exhibited some hygroscopic character.

TABLE 6 Summary of ASD water content (KF) data for ASDs of Example 1.Time Nilotmib:EUDRAGIT L100-55 Nilotinib:HPMC-AS Point 50:50 60:40 70:3080:20 50:50 60:40 70:30 80:20 0 0.7% 1.3% 1.2% 1.2% 1.2% 1.2% 1.2% 1.2%1 week 4.4% 4.1% 4.1% 4.5% 4.7% 5.1% 4.8% 3.5% 2 weeks 4.6% 3.9% 4.0%4.1% 5.4% 4.9% 4.9% 3.7% 4 weeks 4.1% 4.1% 4.3% 4.5% 4.6% 4.1% 4.1% 4.1%Glass Transition Temperature

Modulated differential scanning calorimetry (mDSC) analysis was run on aTA Instruments Model Q200, equipped with a RCS90 refrigerated coolingsystem, to assess glass transition temperatures. In general, about 5-10mg of ASD powder was loaded in a TA T_(zero) low-mass aluminum pan andsealed with a T_(zero) lid. Instrument details and measurementconditions are specified in Table 7. Results are provided in Table 8.

TABLE 7 TA Q200 DSC instrument and measurement conditions. ParameterCondition DSC Model Modulated Test MDSC heat only Method Modulate ±0.48° C. every 60 sec Temperature ramp 3° C./min from 0° C. to 200° C.Data sampling 0.20 sec interval

TABLE 8 Summary of observed glass transition temperature (DSC) data(T_(g)) for ASDs of Example 1. Time Nilotinib:EUDRAGIT L100-55Nilotinib:HPMC-AS Point 50:50 60:40 70:30 80:20 50:50 60:40 70:30 80:200 131.3° C. 130.1° C. 124.5° C. 103.2° C. 101.2° C. 100.6° C. 99.1° C. 98.1° C. 1 week 133.5° C. 132.7° C. 126.5° C. 115.7° C. 101.0° C. 100.5°C. 98.8° C.¹ ND 2 weeks 134.9° C. 131.6° C. 124.3° C. 116.7° C. 101.5°C. 100.2° C. 98.6° C.¹ ND 4 weeks 135.4° C. 134.8° C. 126.2° C. 117.0°C. 100.2° C. ND ND ND 1 possible second T_(g) observed near 60° C. ND =none detected

As can be seen from the results in Table 8, the ASDs comprising EUDRAGITL100-55 exhibited decreasing T_(g) value with increasing drug load. Forall four drug load levels, there was essentially no change in T_(g) onstability.

In the case of the ASDs comprising HPMC-AS, T_(g) values were similaracross the four drug-load levels. The 60:40 ASD had stable T_(g) for thefirst two weeks; however, no T_(g) was detected at four weeks. The 70:30ASD also had a stable T_(g) for the first two weeks; however, a weakthermal event that may indicate a second T_(g) near 60° C. was observed,suggesting that the sample may have been undergoing a phase separationwhile on stability. No T_(g) could be detected for the 80:20 ASD sampleon stability. The lack of a measurable T_(g) for these samples suggestedthat some type of physical change may have occurred with the HPMC-ASASDs held under accelerated conditions during stability testing.

Assay/Related Substances

Assay and related substances (e.g., impurities) were determined using anAgilent 1200 HPLC utilizing an Agilent Poroshell C18 3.0 mm×150 mm×2.7μm column. Sample solutions of each ASD were prepared by accuratelyweighing approximately 50 mg of ASD powder into a 50 ml volumetricflask. The ASD powder was initially dissolved in a flask inapproximately 40 ml of methanol, and then the flask was vortexed andsonicated until the ASD powder was completely dissolved. The sampleflasks were then brought to volume with methanol and mixed well. Thissample solution was then diluted 10× in diluent (50:50 acetonitrile(ACN):0.1% phosphoric acid in water). The final concentration of theanalyte (nilotinib) in the sample was approximately 0.05 mg/ml. Theinstrument and measurement conditions are specified in Table 9, whilethe gradient profile is listed in Table 10.

TABLE 9 HPLC instrument and measurement conditions. Parameter ConditionMobile Phase A 0.29% TEA and 0.1% AA in water Mobile Phase B 0.29% TEAand 0.1% AA in acetonitrile Flow 0.5 ml/min, gradient Injection volume16.0 μL Column temperature 45° Wavelength 260 nm Run-time 40 min TEA =triethylamine AA = acetic acid

TABLE 10 HPLC instrument gradient profile. Time % Mobile % Mobile (min)Phase A Phase B 0 80.0 20.0 5 80.0 20.0 30 20.0 80.0 35 20.0 80.0 3680.0 20.0 40 80.0 20.0

Assay results are provided in Table 11. Assay values for the ASDscomprising EUDRAGIT L100-55 (96.2%-98.4%) and the ASDs comprisingHPMC-AS (96.5%-97.9%) were as expected given the relatively high totalrelated substances levels observed for the as-supplied drug substance(˜2%) and the measured initial water content of the ASD samples (˜1%).In general, all ASDs demonstrated a decrease in assay over time onstability. This decrease was more pronounced for the ASDs comprisingHPMC-AS as compared to the ASDs comprising EUDRAGIT L100-55. Withreference to Table 6, increased moisture content was likely responsiblefor some of the measured potency loss, as ASDs on stability were foundto contain between 4%-5% water after one week, and assay measurementswere not corrected for water content. Nilotinib peaks were abundantenough to enable determination of percent impurities for each sample.

TABLE 11 Summary of assay (HPLC) data for ASDs of Example 1. TimeNilotinib:EUDRAGIT L100-55 Nilotinib:HPMC-AS Point 50:50 60:40 70:3080:20 50:50 60:40 70:30 80:20 0 98.0% 96.3% 96.2% 98.4% 100.8% 97.9%97.2% 96.5% 1 week 96.0% 93.9% 94.8% 92.7%  96.7% 92.9% 93.7% 94.4% 2weeks 91.4% 95.7% 95.5% 94.0% n/a 91.9% 95.0% 94.3% 4 weeks 87.1% 91.1%91.2% 93.3%  91.8% 87.2% 91.3% 85.7% n/a—data not available

Related substances results are provided in Table 12. Levels of relatedsubstances were similar for all eight ASDs at all time points. Based onthis data, the electrospray process did not appear to increase the levelof related substances, and all ASDs appeared chemically stable underaccelerated conditions on stability despite exposure to high levels ofheat and humidity.

TABLE 12 Summary of total related substances (HPLC) data for ASDs ofExample 1. Time Nilotinib:EUDRAGIT L100-55 Nilotinib:HPMC-AS Point 50:5060:40 70:30 80:20 50:50 60:40 70:30 80:20 0 1.9% 2.2% 2.0% 1.9% 1.9%2.1% 2.1% 1.9% 1 week 1.8% 2.4% 2.1% 2.1% 1.6% 2.3% 2.3% 2.0% 2 weeks1.8% 2.3% 2.1% 2.0% 1.9% 2.2% 2.3% 2.0% 4 weeks 1.8% 2.4% 1.9% 1.9% 1.7%2.2% 2.3% 2.0%

Example 2 Stability of Nilotinib ASD Under Accelerated StorageConditions

A study was performed to evaluate the stability of a nilotinib ASDaccording to embodiments of the present disclosure under differentaccelerated storage conditions.

The ASD was prepared similarly to the ASDs described in Example 1,except the solvent mixture was tetrahydrofuran and methanol in a 60:40(v/v) ratio. (The tetrahydrofuran was stabilized with a small quantityof BHT as an antioxidant; therefore, the ASDs prepared in this examplewill contain a small, unquantified amount of BHT along with nilotiniband polymer.) Equal quantities of nilotinib and HPMC-AS were dissolvedin the solvent mixture to prepare a liquid feedstock, which waselectrosprayed to provide the ASD powder.

The resulting ASD powder contained nilotinib and HPMC-AS in a ratio of50:50 (w/w), and was stored under accelerated conditions at 25° C./60%RH for 24 months, and at 40° C./75% RH for six months. The ASD powderwas assessed for each storage condition at t=0 and at 1 month, 2 months,3 months, and 6 months for amorphicity (XRD), water content (KarlFisher), glass transition temperature (DSC), and assay/relatedsubstances (HPLC). For the samples stored at 25° C./60% RH, additionalassessments were done at later time points up to 24 months.

Amorphicity

Amorphicity was assessed as in Example 1, above. The ASD remainedamorphous throughout the entire stability study for both sets of storageconditions.

Water Content

Water content was measured by coulometric Karl Fischer titration, as inExample 1, except that sample size was approximately 50-100 mg of ASDpowder.

As indicated in Table 13, water content remained substantiallyconsistent across stability timepoints, and no adverse hygroscopicity isobserved for the ASDs.

TABLE 13 Summary of water content (KF) data for ASD of Example 2. TimePoint Storage Condition (months) 25° C./60% RH 40° C./75% RH 0 1.52%1.52% 1 3.25% 3.71% 2 3.41% 3.63% 3 3.37% 3.51% 6 3.15% 3.70% 9 0.88% 122.82%Glass Transition Temperature

Glass transition temperature (T_(g)) of the ASD stored under acceleratedconditions was assessed as in Example 1. Results are provided in Table14.

TABLE 14 Summary of glass transition (mDSC) data (T_(g)) for ASD ofExample 2. Time Point Storage Condition (months) 25° C./60% RH 40°C./75% RH 0  98.8° C.  98.8° C. 1 101.7° C. 101.2° C. 2 101.4° C. 101.4°C. 3 100.1° C. 102.8° C. 6 100.2° C. 102.3° C. 9 100.6° C. 12  99.7° C.18 100.5° C. 24 100.6° C.

The results show that, for each storage condition, the glass transitiontemperature of the ASD was generally unchanged over time, whichindicates that the ASD was physically stable.

Assay/Related Substances

Assay and related substances (e.g., impurities) of the ASD were assessedthrough HPLC, utilizing an Agilent Poroshell HPH-C18 3.0 mm×150 mm×2.7μm column. Sample solutions were prepared by accurately weighingapproximately the equivalent of 10 mg of the ASD powder into a 100 mlvolumetric flask. The ASD powder was dissolved in approximately 90 ml ofmethanol:water (80:20). The sample flasks were then brought to volumewith 80:20 methanol:water and mixed well until the ASD powder was fullydissolved. The final concentration of the analyte (nilotinib) in thesample was approximately 0.1 mg/ml. The instrument and measurementconditions are specified in Table 15, while the gradient profile islisted in Table 16.

TABLE 15 HPLC instrument and measurement conditions. Parameter ConditionColumn Agilent Poroshell HPH-C18, 3.0 mm × 150 mm × 2.7 μm Flow rate 0.5ml/min Mobile Phase A 20 mM ammonium bicarbonate, pH 9.0 Mobile Phase BACN:MeOH (80:20) Mobile Phase C ACN:MeOH (90:10) Elution programGradient Injection Volume 5 μL, (assay); 10 μL, (related substances)Column Temperature 45° C. Detector Wavelength 260 nm

TABLE 16 HPLC instrument gradient program. Time % Mobile % MobileAnalysis (min) Phase A Phase B Assay Method 0 55 45 7 30 70 8 0 100 9 0100 9.1 55 45 12 55 45 Related Substances 0 90 10 Method 2 90 10 5 65 3535 52 48 40 0 100 41 0 100 41.1 90 10 44 90 10

Assay values were determined for the ASD post-spray (t=0) and atdesignated stability timepoints under each storage condition. Measuredassay values of the ASD for each storage condition are listed in Table17. The reported assay values are not corrected for water content.

TABLE 17 Summary of assay (HPLC) data for ASD of Example 2. Time PointStorage Condition (months) 25° C./60% RH 40° C/75% RH 0 95.8% 95.8% 193.5% 93.7% 2 95.0% 94.7% 3 95.5% 95.3% 6 95.6% 96.4% 9 97.7% 12 95.0%18 93.3% 24 94.4%

Total related substances measured values for the ASD under each storagecondition are listed in Table 18.

TABLE 18 Summary of total related substances (HPLC) data for ASD ofExample 2. Time Point Storage Condition (months) 25° C./60% RH 40°C./75% RH 0 0.60% 0.60% 1 0.56% 0.63% 2 0.72% 0.81% 3 0.80% 0.78% 60.52% 0.57% 9 0.68% 12 0.71% 18 0.62% 24 0.71%

As demonstrated in Tables 17 and 18, the ASD exhibited suitably highassay values and suitably low related substances values that did notappreciably change over time, indicating that the ASD was chemicallystable.

Example 3 Preparation and Characterization of Nilotinib ASD Granules

A granulated product comprising Nilotinib ASD was fabricated andcharacterized. The fabrication process required several stepsincluding: 1) preparing Nilotinib ASD; 2) preparing a granulation blendcomprising the Nilotinib ASD; 3) roller-compacting the granulation blendto provide Nilotinib ASD Granules. The Nilotinib ASD Granules werecharacterized by bulk and tap density testing and particle sizedistribution analysis.

Nilotinib ASD was prepared with HPMC-AS as the polymer, in a 50:50ratio. The Nilotinib ASD also included 0.34% by weight of BHT as anantioxidant. To prepare the Nilotinib ASD, appropriate quantities ofHPMC-AS (AFFINISOL 912G) and nilotinib (anhydrous) were dissolved in a60:40 (v/v) solvent mixture of tetrahydrofuran (unstabilized) andmethanol to provide a liquid feedstock. An appropriate quantity of BHTwas included (approximately 115 ppm) to provide 0.34% by weight of thetotal solids. The total solids concentration in the feedstock wasapproximately 30 mg/mL.

The resulting feedstock was electrosprayed using the Nanocopoeia ESmachine ENS-FLEX 20. For each spray run, the spray process parameters,such as extractor voltage and flow rate, were adjusted to achieve anacceptable spray plume.

Following the electrospray processing, the Nilotinib ASD (now in theform of a powder) was subjected to a secondary drying procedure toreduce the levels of residual solvents and moisture. For secondarydrying, the powder was placed on drying trays and placed into an ovenwhich was heated to 50° C. The powder material was dried under vacuum(approximately −30 mm Hg) for at least six hours. At the end ofsecondary drying, the vacuum was released with dry nitrogen gas.

A granulation blend comprising the Nilotinib ASD was prepared using thecomponents given in Table 19. The granulation blend components (exceptmagnesium stearate) were first bag-blended for 1 minute, then sievedthrough a 20-mesh screen and charged into a v-blender shell. Thatmixture was then blended using a Patterson Kelley V-Blender for 30minutes at approximately 20-25 RPM. A portion of that blended mixturewas then bag-blended with the magnesium stearate for 1 minute; thismixture was then sieved through a 20-mesh screen and added to thecontents of the v-blender shell. The resulting mixture was blended usingthe PK V-Blender for an additional 5 minutes to provide the granulationblend.

TABLE 19 Components of granulation blend from Example 3. % By Weight ofthe Component Granule Nilotinib ASD (49.83%  60% nilotinib, by weight)Mannitol (PEARLITOL 100 SD)  31% Croscarmellose sodium (VIVASOL)   8%Colloidal silica (AEROSIL R972) 0.5% Magnesium stearate 0.5%

The granulation blend was next roller-compacted and granulated. Rollercompaction was done using a Freund-Vector TFC-LAB Micro Roll CompactionUnit, which had been pre-treated with a blend of inactive ingredients.For roller compaction of the granulation blend, the roller pressure wasset in the range 500-7600 psi, the roller speed was set in the range of1.5-2.5 rpm, and the screw speed was set in the range of 10-20 rpm.Ribbons of compacted material were collected in a collection bin at theroller compactor discharge chute. The collected ribbons were then milledthrough an oscillating granulator fitted with a 24-mesh screen. Granularmaterial passing through was collected (“Nilotinib ASD Granules”).

The Nilotinib ASD Granules were subjected to bulk and tap densitytesting and particle size distribution analysis. Bulk density wasmeasured as 0.53 g/mL and tap density was measured as 0.66 g/mL. Resultsfor particle size distribution tested by sonic sifter are given in

TABLE 20 Particle size distribution of Nilotinib ASD Granules asdetermined by sonic sifter. Mesh Size % Retained  30 Mesh  2.7%  40 Mesh31.1%  50 Mesh 24.3%  60 Mesh  8.0%  80 Mesh  9.4% 100 Mesh  5.4% Fines18.2%

Example 4 Preparation and Characterization of Nilotinib OrallyDisintegrating Tablets

Orally disintegrating tablets comprising the Nilotinib ASD Granules werefabricated and characterized. The fabrication process steps included: 1)preparing a tableting blend comprising the granules; and 2) mechanicallypressing the tableting blend to provide Nilotinib Orally DisintegratingTablets (“Nilotinib ODTs”). Characterization of the Nilotinib ODTsincluded tablet breaking force, tablet friability, and disintegrationtesting.

A tableting blend was prepared using the Nilotinib ASD Granules andother blend components given in Table 21. Each component (exceptmagnesium stearate) was sieved through a 20-mesh screen and charged intoa v-blender shell. That mixture was then blended using a Globe PharmaMaxiBlend blender for 45 minutes at 25 RPM. Magnesium stearate was thensieved through a 20-mesh screen and added to the mixture in thev-blender, and the mixture was blended for an additional 5 minutes toprovide the tableting blend.

TABLE 21 Components of tableting blend from Example 4. % By WeightComponent of the Tablet Nilotinib ASD Granules (29.9% 50.0% nilotinib,by weight) Mannitol (PEARLITOL 100 SD) 39.2% Croscarmellose sodium(VIVASOL)  4.0% Crospovidone (KOLLIDON CL-SF)  4.0% Microcrystallinecellulose  2.0% (AVICEL PH-102) Colloidal silica (AEROSIL R972)  0.3%Magnesium stearate  0.5%

The tableting blend was then used to prepare Nilotinib ODTs havingnominally 25 mg nilotinib, 40 mg nilotinib, 60 mg nilotinib, 75 mgnilotinib, and 100 mg nilotinib. Tablets were mechanically compressedusing a Korsch XL-100 Tablet Press operating at a turret speed of 20rpm. Tableting parameters are provided in Table 22.

TABLE 22 Tableting parameters for Nilotinib ODTs from Example 4. TargetTablet Compression Nominal Dosage Weight Tooling Force  25 mg NilotinibODT 167 mg  7 mm round 2.7 kN  40 mg Nilotinib ODT 267 mg  9 mm round3.9 kN  60 mg Nilotinib ODT 400 mg 11 mm round 5.7 kN  75 mg NilotinibODT 500 mg 11 mm round 5.6 kN 100 mg Nilotinib ODT 667 mg 13 mm round7.3 kN

The fabricated Nilotinib ODTs were characterized to assess tabletbreaking force, tablet friability, and disintegration time.Characterization results are provided in Table 23. Tablet breaking forcetesting was performed according to USP <1217> Tablet Breaking Forceusing a Sotax MT50 Tablet Hardness Tester; the reported ranges representresults for 25-35 tablets tested. Tablet friability testing wasperformed according to USP <1216> Tablet Friability, using a suitabletablet friabilator apparatus. Disintegration time was assessed accordingto USP <701> Disintegration, using a Sotax DT50 Disintegration Tester.

TABLE 23 Characterization results for Nilotinib ODTs from Example 4.Tablet Breaking Disintegration Force Friability Time  40 mg NilotinibODT 3.0-4.5 kp 0.00% 15 sec  40 mg Nilotinib ODT 2.7-3.8 kp 0.40% 15 sec 60 mg Nilotinib ODT 4.9-6.1 kp 0.21% 15 sec  75 mg Nilotinib ODT5.6-6.7 kp 0.14% 21 sec 100 mg Nilotinib ODT 4.2-5.4 kp 0.67% 15 sec

In addition, 75 mg Nilotinib ODT dosage units were placed underaccelerated conditions at 40° C./75% RH open dish and also 40°C./protected (where “protected” means dosage units were sealed in foilpouches and placed in a controlled 75% RH chamber for the storageperiod). The storage period was 3 months. At t=0, 2 weeks, 2 month, and3 months, the dosage units were observed for appearance and assessed forcrystallinity, glass transition temperature, water content, assay andtotal related substances, using similar methods to prior examples.

All samples passed visual appearance examination, with no visiblechanges over 3 months. Glass transition was determined to be Tg=100.5°C. at t=0, and did not change significantly over three months. Nocrystallinity was detected at t=0 or at any time during the storageperiod.

With respect to water content, the measured water content at t=0 was1.75% by weight. The sample stored at 40° C./75% RH did show increase inwater content, rising to 3.98% over 3 months. The 40° C./protectedsample was far less susceptible to atmospheric moisture, with a measuredwater content of 1.42% after 3 months.

Assay results (corrected for water content) for all samples were atleast 98% throughout the storage period.

These characterization and stability results indicate that thefabricated Nilotinib ODTs are quite well suited as orally disintegratingtablets for the delivery of nilotinib.

Example 5 In Vitro Dissolution of Orally Disintegrating Tablets

Dissolution testing was performed to assess the performance of thenilotinib orally disintegrating tablets of the disclosure. Comparativedissolution testing was done with TASIGNA IR Capsules to assess therelative performance of the orally disintegrating tablets of thedisclosure. Dissolution testing was done both at pH 1 and at pH 3.

Dissolution testing at pH 1 was conducted using a hydrochloric acid (0.1N; pH 1) dissolution medium, based on the method published for nilotinibimmediate-release capsules in FDA's Dissolution Methods Database. ForTASIGNA IR Capsules, the test was done according to USP <711>Dissolution using Apparatus 1 (Basket Apparatus; 100 rpm). For 75 mgNilotinib ODT, the test was done according to USP <711> Dissolutionusing Apparatus 2 (Paddle Apparatus; 50 rpm). For each pH 1 dissolutiontest, the quantity of medium used was 1000 mL. Samples were pulled at 10min, 15 min, 30 min, and 45 min. Quantitation of nilotinib was performedby reverse-phase HPLC using methods similar to preceding examples.

Results of pH 1 dissolution testing for 75 mg Nilotinib ODT and forTASIGNA IR Capsules are provided in Table 24. Both the Nilotinib ODT andthe TASIGNA IR Capsules released a substantial fraction of nilotinib by10 minutes, with substantially complete dissolution within 45 minutes.This result was not surprising, given the known solubility of nilotinibat pH 1.

TABLE 24 Dissolution results at pH 1 for Nilotinib ODT from Example 4and for TASIGNA IR Capsules. % Dissolved (relative to nominal nilotinibcontent) 75 mg TASIGNA Nilotinib IR Time ODT Capsules  0 0 0 10 min 8575 15 min 93 98 30 min 95 99 45 min 96 100

Dissolution testing at pH 3 was conducted according to USP <711>Dissolution using Apparatus 2 (Paddle Apparatus; 100 rpm) with a maleatebuffer (20 mM; pH 3) as dissolution medium. The quantity of medium usedwas set to 100 mL per 20 mg of the label claim for the test dosage unit.(By way of example, dissolution testing of a dosage unit containingnominally 100 mg nilotinib would be done using 500 mL of dissolutionmedium.)

Dissolution testing of the 75 mg Nilotinib ODT was done by adding theintact dosage unit to the dissolution vessel. The comparativedissolution testing of TASIGNA IR Capsules was done by emptying thecontents of 200 mg TASIGNA capsules and weighing out a portioncorresponding to nominally 75 mg nilotinib. The measured portion wasadded to the dissolution vessel in the form of a powder. Samples werepulled at 10 min, 15 min, 30 min, and 45 min. Quantitation of nilotinibwas performed by reverse-phase HPLC using methods similar to precedingexamples.

Results of pH 3 dissolution testing for 75 mg Nilotinib ODT and forTASIGNA IR Capsule powder are provided in Table 25. At each time pointafter initiation of the test, the Nilotinib ODT released substantiallymore nilotinib into the pH 3 dissolution medium than the TASIGNA IRCapsule powder. This result demonstrates that the orally disintegratingtablets provided by the present disclosure are capable of deliveringnilotinib under higher pH conditions, despite the known poor inherentsolubility of nilotinib under these conditions.

TABLE 25 Dissolution results at pH 3 for Nilotinib ODT from Example 4and for TASIGNA IR Capsule powder. % Dissolved (relative to nominalnilotinib content) 75 mg TASIGNA Nilotinib IR Capsule Time ODT powder  00.0 0.0 10 min 10.1 1.0 15 min 13.8 1.3 30 min 17.8 1.5 45 min 16.3 1.5

Example 6 Human In Vivo Pharmacokinetic and Relative BioavailabilityStudies Under Fasted Conditions

A study was performed in human subjects to assess the pharmacokineticsobserved upon administration of Nilotinib ODT (60 mg, 75 mg, and 100 mg)compositions under fasted conditions, as compared to pharmacokineticsobserved upon administration of commercially available conventionalimmediate-release nilotinib capsules under fasted conditions.

Healthy subjects were orally administered either TASIGNA IR Capsule (200mg) or Nilotinib ODT (60 mg, 75 mg, or 100 mg) in accordance with theregimens described in Table 26. The study employed a crossover studydesign, in which each subject participated in each regimen for eachperiod of the study.

TABLE 26 Human in vivo dosing regimens under fasted conditions. NominalAdmin- Nilotinib istration Regimen Study Product Dosage Condition ATASIGNA IR Capsule 200 mg fasted B  60 mg Nilotinib ODT  60 mg fasted C 75 mg Nilotinib ODT  75 mg fasted D 100 mg Nilotinib ODT 100 mg fasted

Subjects were screened for inclusion in the study up to 28 days beforedosing. Each study period followed the same design. Subjects wereadmitted to the clinical unit on the morning of the day prior toadministration of the study product (Day −1) where eligibility wasreviewed and confirmed. After an overnight fast of a minimum of 10hours, subjects were dosed on the morning of Day 1 of each period, andsubjects continued to fast for approximately 4 hours post-dose. Subjectsremained on site for the first 48 hours post-dose and returned to theclinical unit for a pharmacokinetic blood sample and safety assessmentsat 72 hours post-dose. There was a minimum washout of 7 days betweeneach study period.

A subject was considered evaluable for the pharmacokinetic/effectivebioequivalence assessment if the subject received the reference product(TASIGNA IR Capsule) and at least one of the test products (60 mg, 75mg, or 100 mg Nilotinib ODT) in the fasted state, and if pharmacokineticand safety data up to 72 hours post-dose were obtained. An initial setof 26 subjects was dosed according to Regimen A; however, due to studywithdrawals and other factors, the number of evaluable subjects forRegimen A was 25, and for Regimens B through D the number of evaluablesubjects was either 22 or 23.

Following oral administration, blood samples were taken at the followingtime points to assess the plasma concentration of nilotinib: 0 (prior toadministration), 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, 24, 36, 48, and72 hours. Plasma concentration of nilotinib was determined using avalidated liquid chromatography-tandem mass spectrometry method.

Key pharmacokinetic parameters were calculated for each regimen usingpooled data for evaluable subjects. Statistical analysis was performedusing natural log-transformed C_(max) and AUC values. (Note that forRegimen D, an interim statistical analysis was performed on data from asubset of 20 subjects due to the unavailability of data for two subjectsat the time of the statistical analysis. The following results are basedon this subset (n=20) of the full set of evaluable subjects.)

Table 27 provides the geometric means and coefficients of variation (CV%) for key pharmacokinetic parameters determined for the dosingregimens. Table 28 provides geometric means and coefficients ofvariation (CV %) of non-dose adjusted relative bioavailabilities (Frel)in subjects following administration of each regimen.

Under fasted conditions, Regimens B and C exhibited AUC and C_(max)values that are somewhat lower than the AUC and C_(max) attained byRegimen A (200 mg TASIGNA IR Capsule). However, Regimens B and C weredosed at 60 mg and 75 mg nilotinib, respectively, as compared to the 200mg TASIGNA IR Capsule dosed in Regimen A.

Comparing Regimen C (75 mg Nilotinib ODT) to Regimen D (100 mg NilotinibODT), an increase in the dose of Nilotinib ODT formulation from 75 to100 mg resulted in an increase in exposure, with geometric mean C_(max),AUC₍₀₋₂₄₎, AUC_((0-last)) and AUC_((0-inf)) increasing by 20%, 23%, 34%and 34% respectively for the 33% increase in nominal dosage.

Under fasting conditions, Regimen D (100 mg Nilotinib ODT) exhibited AUCand C_(max) values that are quite comparable to the AUC and C_(max)attained by Regimen A (200 mg TASIGNA IR Capsule), even though thenominal nilotinib dosage for Regimen D is half that of the nominaldosage for Regimen A. The geometric mean of the individual subjectrelative bioavailabilities of nilotinib following administration ofRegimen D were 97.3% based on C_(max), 99.0% based on AUC₍₀₋₂₄₎, 94.2%based on AUC_((0-last)) and 94.1% based on AUC_((0-inf)), relative toRegimen A. (See Table 28.)

An intermediate effective bioequivalence analysis was performedcomparing Regimen D (100 mg Nilotinib ODT) as the test composition toRegimen A (200 mg TASIGNA IR Capsule) as the reference composition. Amixed-effects modeling technique was first performed to determineadjusted means and differences for pairwise comparisons. The adjustedmeans and differences obtained from the models, along with theirassociated 90% confidence intervals (CIs), were back-transformed on thelog scale to obtain adjusted geometric mean ratios (GMRs) and respective90% confidence intervals of the ratios. Relevant calculated values arereported in Table 29. Ratios are presented as Test/Reference.

For each relevant parameter, peak exposure (represented by C_(max)) andoverall exposure (represented by AUC₍₀₋₂₄₎, AUC_((0-last)) andAUC_((0-inf))) obtained for the test composition of Regimen D weresimilar to the reference composition of Regimen A; i.e., the ratios wereclose to 100%. (A ratio of 100% represents no difference between testand reference regimens.) The 90% confidence interval values suggestthat, for all of the relevant parameters, it is likely that the trueratios are above 83% and below 108%. The p-values indicate that there isan absence of a statistically meaningful difference between the twotreatments (i.e., they can be considered “effectively bioequivalent).

From these results, it can be concluded that the 100 mg Nilotinib ODT ofthe present disclosure is effectively bioequivalent to commerciallyavailable conventional immediate-release nilotinib capsules having 200mg nilotinib (i.e., 200 mg TASIGNA IR Capsule).

TABLE 27 Geometric mean (coefficient of variation, or CV%) keypharmacokinetic parameters of nilotinib in healthy volunteers followingoral administration of TASIGNA IR Capsule and Nilotinib ODT compositionsaccording to embodiments of the disclosure. T_(max)* C_(max) AUC₍₀₋₁₂₎AUC₍₀₋₂₄₎ AUC_((0-last)) AUC_((0-inf)) t_(1/2) Regimen (h) (ng/ml) (ng ·h/ml) (ng · h/ml) (ng · h/ml) (ng · h/ml) (h) A: 200 mg TASIGNA 4.00 5424340 7090 11100 12000 14.9 IR Capsule—fasted (2.00-8.00) (30.2) (30.7)(32.3) (43.1) (41.5) (35.6)  B: 60 mg Nilotinib ODT—fasted 2.00 444 36905740 8360 8570 12.7 (1.00-5.00) (26.9) (21.7) (24.6) (32.3) (33.5)(27.1)  C: 75 mg Nilotinib ODT—fasted 2.00 455 3740 5820 8220 8650 14.1(1.00-4.00) (26.3) (23.4) (25.6) (30.1) (30.1) (31.3) D: 100 mgNilotinib ODT—fasted 2.00 546 4560 7170 11000 11600 15.3 (1.00-5.00)(30.6) (24.9) (26.8) (32.2) (33.4) (31.0) *median (range)

TABLE 28 Geometric mean (CV %) relative bioavailabilities (F_(rel)) ofnilotinib in healthy volunteers following oral administration of testcompositions (Nilotinib ODT compositions according to the disclosure),relative to reference composition (TASIGNA IR Capsule). F_(rel) F_(rel)F_(rel) F_(rel) C_(max) AUC₍₀₋₂₄₎ AUC_((0-last)) AUC_((0-inf)) TestRegimen Reference Regimen (%) (%) (%) (%) B: 60 mg Nilotinib A: 200 mgTASIGNA 80.1 79.0 70.9 68.7 ODT-fasted IR Capsule-fasted (23.2) (24.2)(28.7) (30.2) C: 75 mg Nilotinib A: 200 mg TASIGNA 83.2 79.9 69.6 69.1ODT-fasted IR Capsule-fasted (31.6) (29.9) (33.7) (35.6) D: 100 mgNilotinib A: 200 mg TASIGNA 97.3 99.0 94.2 94.1 ODT-fasted IRCapsule-fasted (32.8) (29.7) (33.9) (36.0)

TABLE 29 Intermediate effective bioequivalence analysis for oraladministration under fasted conditions of a test composition (100 mgNilotinib ODT) compared to reference composition (TASIGNA IR Capsule).Adjusted Geometric Mean Ratio (%) Pharmacokinetic (Test/ 90% ConfidenceCV_(w) * Comparison Parameter Reference) Interval p-value (%) Test (100mg Nilotinib C_(max) (ng/ml) 98.02 (89.79, 107.00) 0.70 17.33ODT-fasted) vs. AUC₍₀₋₂₄₎ (ng · h/ml) 98.74 (90.50, 107.73) 0.81 17.23Reference (200 mg AUC_((0-last)) (ng · h/ml) 93.49 (84.36, 103.61) 0.2820.37 TASIGNA IR AUC_((0-inf)) (ng · h/ml) 93.27 (83.65, 103.99) 0.2921.60 Capsule-fasted) * within-subject variation

Example 7 Human In Vivo Pharmacokinetic and Relative BioavailabilityStudy Under Fed Conditions

A study was performed in human subjects to assess the pharmacokineticsobserved upon administration of 100 mg Nilotinib ODT composition underfed conditions. Comparison was made to pharmacokinetics observed uponadministration of commercially available conventional immediate-releasenilotinib capsules under fasted conditions (Regimen A from Example 6).Further comparison was made between the pharmacokinetics observed uponadministration of 100 mg Nilotinib ODT composition under fed conditions,as compared to pharmacokinetics observed upon administration of 100 mgNilotinib ODT composition under fasted conditions (Regimen D fromExample 6). Table 30 indicates the relevant regimens involved in thisstudy.

TABLE 30 Human in vivo dosing regimens under fed vs. fasted conditions.Nominal Nilotinib Administration Regimen Study Product Dosage ConditionA TASIGNA IR Capsule 200 mg fasted D 100 mg Nilotinib ODT 100 mg fastedF 100 mg Nilotinib ODT 100 mg fed

Regimens A and D were conducted as described in Example 6. Regimen F wasconducted using the same set of healthy subjects using a crossover studydesign. Regimen F was conducted similarly to the regimens described inExample 6, except that following the overnight fast, subjects were fed ahigh-fat breakfast 30 minutes prior to dosing. Subjects were instructedto eat the meal within a maximum period of 20 minutes, and were requiredto consume at least 95% of the provided meal. After dosing, a lunch mealwas then provided approximately 4 hours post-dose, an evening meal wasprovided approximately 10 hours post-dose, and an evening snack wasprovided approximately 14 hours post-dose.

A subject was considered evaluable for the pharmacokinetic/effectivebioequivalence assessment if the subject received the reference product(TASIGNA IR Capsule) in the fasted state, and the test product (100 mgNilotinib ODT) in the fed state, and if pharmacokinetic and safety dataup to 72 hours post-dose were obtained. The number of evaluable subjectsfor Regimen F was 21. Key pharmacokinetic parameters were calculated foreach regimen using pooled data for evaluable subjects. Statisticalanalysis was performed using natural log-transformed C_(max) and AUCvalues.

Table 31 provides the geometric means and coefficients of variation (CV%) for key pharmacokinetic parameters determined for the relevant dosingregimens. Table 32 provides geometric means and coefficients ofvariation (CV %) of non-dose adjusted relative bioavailabilities (Frel)in subjects for test Regimen F, as compared to the reference Regimen A.

With respect to maximum blood concentrations, Regimen F (100 mgNilotinib ODT, fed) exhibited a geometric mean C_(max) value that wasvery close to the geometric mean C_(max) value observed for Regimen A(200 mg TASIGNA IR Capsule, fasted), with Frel of 102 (CV 31.3%). Thegeometric mean C_(max) value for Regimen F (100 mg Nilotinib ODT, fed)was also very close to the geometric mean C_(max) value observed forRegimen D (100 mg Nilotinib ODT, fasted), These data indicate thatcompositions according to the disclosure may be capable of providingtherapeutic concentrations under fed conditions, and did not exhibit asignificant food effect with respect to C_(max).

With respect to exposure, Regimen F exhibited somewhat higher AUC valuesthan Regimen A, with AUC₍₀₋₂₄₎, AUC_((0-last)) and AUC_((0-inf)) allincreased by 17-24% relative to Regimen A (Table 32). Taken togetherwith the fasted results from Regimen D (discussed in Example 6), thisindicates that the compositions of the disclosure may be suitable toprovide a therapeutic exposure of nilotinib, at a greatly reduced dose(compared to the reference composition).

As shown in Table 31, Regimen F (100 mg Nilotinib ODT, fed) alsoexhibited somewhat higher AUC values as compared to Regimen D (100 mgNilotinib ODT, fasted), indicating a slight positive food effect withrespect to exposure for the 100 mg Nilotinib ODT composition.

An intermediate effective bioequivalence analysis was performedcomparing Regimen F (100 mg Nilotinib ODT, fed) as the test compositionto Regimen A (200 mg TASIGNA IR Capsule, fasted) as the referencecomposition. A mixed-effects modeling technique was first performed todetermine adjusted means and differences for pairwise comparisons. Theadjusted means and differences obtained from the models, along withtheir associated 90% confidence intervals (CIs), were back-transformedon the log scale to obtain adjusted geometric mean ratios (GMRs) andrespective 90% confidence intervals of the ratios.

Relevant calculated values are reported in Table 33. Ratios arepresented as Test/Reference. For the intermediate effectivebioequivalence analysis, the adjusted geometric mean ratio for C_(max)was 101.38 and the 90% confidence interval range fell within the 80-125%range typically used for bioequivalence analysis. However, the adjustedgeometric mean ratios for AUC₍₀₋₂₄₎, AUC_((0-last)) and AUC_((0-inf))all exceeded 117 and the 90% confidence interval range did not fallwithin the 80-125% range. Therefore, although the adjusted geometricmean C_(max) observed for the test regimen closely matched that for thereference regimen, the AUC values were somewhat increased, and soRegimen F (100 mg Nilotinib ODT, fed) could not statistically beconsidered as effectively bioequivalent to Regimen A (200 mg TASIGNA IRCapsule, fasted).

Similarly, an intermediate effective bioequivalence analysis wasperformed comparing Regimen F (100 mg Nilotinib ODT, fed) as the testcomposition to Regimen D (100 mg Nilotinib ODT, fasted) as the referencecomposition. Relevant calculated values are reported in Table 34. Forthe intermediate effective bioequivalence analysis, the adjustedgeometric mean ratio for C_(max) was 103.31 and the 90% confidenceinterval range fell within the 80-125% range typically used forbioequivalence analysis. However, the adjusted geometric mean ratios forAUC₍₀₋₂₄₎, AUC_((0-last)) and AUC_((0-inf)) all exceeded 120, and the90% confidence interval range did not fall within the 80-125% range.Therefore, although the adjusted geometric mean C_(max) observed for thetest regimen closely matched that for the reference regimen, the AUCvalues were somewhat increased, and so Regimen F (100 mg Nilotinib ODT,fed) could not be statistically considered as effectively bioequivalentto Regimen D (100 mg Nilotinib ODT, fasted). The results shown in Table34 further indicate the slight positive food effect with respect toexposure for the 100 mg Nilotinib ODT product, and an insignificant foodeffect with respect to C_(max). However, these results were asubstantial improvement as compared to the significant food effectreported for TASIGNA. As stated above, reported results for TASIGNAindicate that for a single 400-mg dose of TASIGNA taken 30 minutes aftera high-fat meal, an increase in AUC and C_(max) by 82% and 112%(respectively), was observed, as compared to levels obtained underfasting conditions.

As noted above, a sizable increase in C_(max) between fasted and fedstates may be highly undesirable and potentially unsafe due to increasedrisk of deleterious effects, such as an increased risk of QTprolongation. Therefore, the formulations of the disclosure may besuitable to reduce or eliminate the possibility that a patient mayexperience an undesirably high C_(max) and any deleterious effects thatmight be experienced as a result.

The improvement in food effect was an unexpected and highly advantageousresult obtained by the compositions of the present disclosure. Inproviding a dosage form that can be taken with food, without food, orwithout regard to consumption of food, the present disclosure provides asignificant advance over formulations currently available for theadministration of nilotinib.

TABLE 31 Geometric mean (CV%) key pharmacokinetic parameters ofnilotinib in healthy volunteers following oral administration of 200 mgTASIGNA IR Capsule under fasted conditions, and 100 mg Nilotinib ODTcompositions administered under fasted (Regimen D) and fed (Regimen F)conditions. T_(max)* C_(max) AUC₍₀₋₁₂₎ AUC₍₀₋₂₄₎ AUC_((0-last))AUC_((0-inf)) t_(1/2) Regimen (h) (ng/ml) (ng · h/ml) (ng · h/ml) (ng ·h/ml) (ng · h/ml) (h)   A: 200 mg TASIGNA 4.00 542 4340 7090 11100 1200014.9 IR Capsule—fasted (2.00-8.00) (30.2) (30.7) (32.3) (43.1) (41.5)(35.6) D: 100 mg Nilotinib 2.00 546 4560 7170 11000 11600 15.3ODT—fasted (1.00-5.00) (30.6) (24.9) (26.8) (32.2) (33.4) (31.0) F: 100mg Nilotinib 5.00 572 4780 8660 14700 15600 15.2 ODT—fed (3.00-24.0)(22.9) (20.9) (19.9) (27.6) (30.5) (28.8) *median (range)

TABLE 32 Geometric mean (CV %) relative bioavailabilities (F_(rel)) ofnilotinib in healthy volunteers following oral administration of testcomposition (100 mg Nilotinib ODT) under fed conditions (Regimen F),relative to reference composition (200 mg TASIGNA IR Capsule)administered under fasted conditions (Regimen A). F_(rel) F_(rel)F_(rel) F_(rel) C_(max) AUC₍₀₋₂₄₎ AUC_((0-last)) AUC_((0-inf)) TestRegimen Reference Regimen (%) (%) (%) (%) F: 100 mg Nilotinib A: 200 mgTASIGNA 102 117 124 123 ODT-fed IR Capsule-fasted (31.3) (25.7) (29.8)(31.4)

TABLE 33 Intermediate effective bioequivalence analysis for oraladministration of a test composition (100 mg Nilotinib ODT) under fedconditions, compared to administration of reference composition (200 mgTASIGNA IR Capsule) under fasted conditions. Adjusted Geometric MeanRatio (%) Pharmacokinetic (Test/ 90% Confidence CV_(w) * ComparisonParameter Reference) Interval p-value (%) Test (100 mg Nilotinib C_(max)(ng/ml) 101.38 (92.39, 111.24) 0.81 18.83 ODT-fed) vs. AUC₍₀₋₂₄₎ (ng ·h/ml) 117.28 (108.14, 127.19) 0.002 16.43 Reference (200 mgAUC_((0-last)) (ng · h/ml) 123.48 (112.55, 135.47) <0.001 18.80 TASIGNAIR AUC_((0-inf)) (ng · h/ml) 123.28 (112.04, 135.65) <0.001 19.40Capsule-fasted) * within-subject variation

TABLE 34 Intermediate effective bioequivalence analysis for oraladministration of 100 mg Nilotinib ODT under fed conditions as comparedto administration under fasted conditions. Adjusted Geometric Mean Ratio(%) Pharmacokinetic (Test/ 90% Confidence CV_(w) * Comparison ParameterReference) Interval p-value (%) Test (100 mg Nilotinib C_(max) (ng/ml)103.31 (93.98, 113.58) 0.569 18.83 ODT-fed) vs. AUC₍₀₋₂₄₎ (ng · h/ml)120.25 (110.70, 130.63) <0.001 16.43 Reference (100 mg AUC_((0-last))(ng · h/ml) 135.06 (122.87, 148.45) <0.001 18.80 Nilotinib ODT-fastedAUC_((0-inf)) (ng · h/ml) 135.75 (123.14, 149.65) <0.001 19.40 *within-subject variation

Example 8 Preparation and Characterization of Alternative NilotinibOrally Disintegrating Tablets

A number of alternative formulations for orally disintegrating tabletswere fabricated and characterized. In particular, these formulationswere made with varying filler combinations and ratios, varyingdisintegrant combinations and ratios, and with and without SLS. Theorally disintegrating tablets were prepared as outlined below using adirect compression method.

Orally disintegrating tablets were fabricated and characterized. Thefabrication process steps included: 1) preparing Nilotinib ASD; 2)preparing a tableting blend comprising the ASD; and 3) pressing thetableting blend to provide Nilotinib Orally Disintegrating Tablets(“Nilotinib ODTs”). Characterization of the Nilotinib ODTs was limitedto dissolution testing, due to limited availability of material.

Nilotinib ASD was prepared with HPMC-AS (AFFINISOL 912G) as the polymer,in a 50:50 ratio. The Nilotinib ASD also included between 0.1% and 0.5%by weight of BHT as an antioxidant. The Nilotinib ASD was prepared anddried by a process similar to that described in Example 3.

Tableting blends comprising the Nilotinib ASD were then prepared usingthe components given in Table 35. The tableting blend components (exceptmagnesium stearate) were first blended in a small-scale high shear mixerfor 1 to 5 minutes. Magnesium stearate (when present) was then sievedthrough a 20-mesh screen and added to the mixture in the mixer, and themixture was blended for an additional 1 to 5 minutes to provide thetableting blend.

TABLE 35 Components of tableting blend for orally disintegrating tabletsfrom Example 8. Tableting Blend % by Weight of Tablet Component 11-111-2 11-3 16-1 13-3 18-3 Nilotinib ASD 30.0 30.0 30.0 30.0 30.0 30.0Microcrystalline Cellulose 14.5 29.5 44.5 30.5 30.5 31.0 (AVICEL PH 101)PEARLITOL FLASH 45.0 30.0 15.0 30.0 — 30.0 PEARLITOL 100 SD — — — — 30.0— Croscarmellose Sodium 4.0 4.0 4.0 4.0 4.0 (VIVASOL) Crospovidone 4.04.0 4.0 4.0 4.0 8.0 (KOLLIDON CL-SF) Sodium Lauryl Sulfate 1.0 1.0 1.0 —— — Colloidal Silica 1.0 1.0 1.0 1.0 1.0 1.0 (AEROSIL 200 PHARMA)Magnesium Stearate 0.5 0.5 0.5 0.5 0.5 —

The tableting blends were then used to prepare Nilotinib ODTs having atarget tablet weight of 400 mg (nominally 60 mg nilotinib). Tablets wereeither manually compressed using a portable press (such as Globe Pharmamanual MTCM-1 tablet press), or mechanically pressed using a rotarypress (such as Piccola press).

The fabricated Nilotinib ODTs were characterized to assess in vitrodissolution. Although full data is not provided here, each exemplaryformulation provided adequate release of nilotinib by in vitrodissolution testing using appropriate media.

Although full characterization data was not obtained, based on priorexperience each exemplary formulation is expected to provide an orallydisintegrating tablet with a tablet breaking force in the range of 2 to18 kp, friability less than 1.5%, and disintegration time less than 40seconds. It was concluded that the fabricated Nilotinib ODTs areappropriate as orally disintegrating tablets for the delivery ofnilotinib.

Further, it was determined through these experiments that, although allfillers and disintegrants tested were suitable, a slightly betterperformance was observed using a combination of PEARLITOL FLASH andmicrocrystalline cellulose as fillers. It was also determined (comparingto other formulations not shown above) that the formulation was notsensitive to different grades of microcrystalline cellulose (AVICEL PH101 vs. AVICEL PH 102), so the grades are considered interchangeable.Further, it was determined that crospovidone was adequate by itself as adisintegrant, although combinations may be suitably employed. It wasalso observed that better in vitro dissolution release was realized witha relatively higher amount of crospovidone.

Example 9 Preparation and Characterization of Optimized Nilotinib OrallyDisintegrating Tablets

Orally disintegrating tablets made using an optimized formulation werefabricated and characterized. The orally disintegrating tablets wereprepared using a dry granulation method similar to the process outlinedin Examples 3 and 4, except that the v-blender was equipped with an“I-bar” during blending steps. It was observed that blend uniformity inparticular was improved by use of the I-bar during blending.

The optimized formulation included a combination of PEARLITOL FLASH andmicrocrystalline cellulose as fillers, crospovidone as both anintra-granular and tablet (extra-granular) disintegrant, and a higherproportion of granules relative to extra-granular excipients. (The term“optimized” here does not denote that the formulation is an optimumformulation, but that it was developed through a systematic process toimprove performance and processability.) The optimized formulation isprovided in Table 36.

TABLE 36 Components of optimized formulation for orally disintegratingtablet of Example 9. % by Weight Component of Tablet GranulationNilotinib ASD 30.07 Blend Microcrystalline Cellulose 30.59 (AVICEL PH101) PEARLITOL FLASH 30.59 Crospovidone (KOLLIDON CL-SF) 6.00 ColloidalSilica (AEROSIL 200 PHARMA) 1.00 Magnesium Stearate 0.50 Extra-granularCrospovidone (KOLLIDON CL-SF) 1.00 Excipients Magnesium Stearate 0.25

The optimized formulation was used to prepare Optimized Nilotinib ODTshaving a nominal nilotinib dosage of 60 mg and a target tablet weight of400 mg. (Further work is planned for manufacture of nominal 15 mgOptimized Nilotinib ODTs and nominal 45 mg Optimized Nilotinib ODTs forpossible use in the human clinical studies described below.)

The 60 mg Optimized Nilotinib ODT was characterized using appropriatetests as described above. Tablet weight was found to be on target at 400mg; tablet breaking force was measured in the range of 6 to 10 kp;friability was measured as 0.19%; and disintegration time was measuredto be 25 seconds (n=3). In vitro dissolution testing demonstrated arelease of 63% of the nilotinib within 30 minutes in a dissolutionmedium at pH 3.1. It was concluded that the Optimized Nilotinib ODTs arehighly suitable as orally disintegrating tablets for the delivery ofnilotinib.

The 60 mg Optimized Nilotinib ODT was dosed in human clinical studiessimilar to the studies described in Examples 6 and 7. Clinical data wasnot available at the time of this filing. The 60 mg Optimized NilotinibODT is expected to perform comparably to the 100 mg Nilotinib ODT insuch studies; however, an adaptive study design is employed so that thedose can be adjusted in order to establish bioequivalence to TASIGNA IRCapsules under appropriate conditions as suitable (e.g., fasted; fedconditions with low/medium/high-fat meals; drug-drug interaction studiesusing antacids and/or suitable ARAs).

The foregoing description is given for clearness of understanding only,and no unnecessary limitations should be understood therefrom. Variousmodifications and alterations to this disclosure will become apparent tothose skilled in the art without departing from the scope and spirit ofthis disclosure. It should be understood that this disclosure is notintended to be unduly limited by the illustrative embodiments andexamples set forth herein, and such examples and embodiments arepresented by way of example only.

Reference throughout this specification to “one embodiment,” “anembodiment,” “certain embodiments,” or “some embodiments,” etc., meansthat a particular feature, configuration, composition, or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the disclosure. Thus, the appearances of such phrases invarious places throughout this specification are not necessarilyreferring to the same embodiment of the disclosure. Furthermore, theparticular features, configurations, compositions, or characteristicsmay be combined in any suitable manner in one or more embodiments.

Throughout the specification, where compositions are described asincluding components or materials, it is contemplated that thecompositions can also consist essentially of, or consist of, anycombination of the recited components or materials, unless describedotherwise. Likewise, where methods are described as including particularsteps, it is contemplated that the methods can also consist essentiallyof, or consist of, any combination of the recited steps, unlessdescribed otherwise.

The practice of a method disclosed herein, and individual steps thereof,can be performed manually and/or with the aid of or automation providedby electronic equipment. Although processes have been described withreference to particular embodiments, a person of ordinary skill in theart will readily appreciate that other ways of performing the actsassociated with the methods may be used. For example, the order ofvarious steps may be changed without departing from the scope or spiritof the method, unless described otherwise. In addition, some of theindividual steps can be combined, omitted, or further subdivided intoadditional steps.

The term “comprises” and variations such as “comprises” and “comprising”do not have a limiting meaning where these terms appear in thedescription and claims. Such terms will be understood to imply theinclusion of a stated step or element or group of steps or elements butnot the exclusion of any other step or element or group of steps orelements.

By “consists of” (or similarly “consisting of”) is meant including, andlimited to, whatever follows the phrase “consists of.” Thus, the phrase“consists of” in dictates that the listed elements are required ormandatory, and that no other elements may be present. By “consistsessentially of” (or similarly “consisting essentially of”) is meantincluding any elements listed after the phrase, and limited to otherelements that do not interfere with or contribute to the activity oraction specified in the disclosure for the listed elements. Thus, thephrase “consists essentially of” indicates that the listed elements arerequired or mandatory, but that other elements are optional and may ormay not be present depending upon whether or not they materially affectthe activity or action of the listed elements.

The words “preferred” and “preferably” refer to embodiments of thedisclosure that may afford certain benefits, under certaincircumstances. However, other embodiments may also be preferred, underthe same or other circumstances. Furthermore, the recitation of one ormore preferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the disclosure.

In this application, terms such as “a,” “an,” and “the” are not intendedto refer to only a singular entity, but include the general class ofwhich a specific example may be used for illustration. The terms “a,”“an,” and “the” are used interchangeably with the term “at least one.”The phrases “at least one of” and “comprises at least one of” followedby a list refer to any one of the items in the list and any combinationof two or more items in the list.

As used herein, the term “or” is generally employed in its usual senseincluding “and/or” unless the content clearly dictates otherwise. Theterm “and/or” means one or all of the listed elements or a combinationof any two or more of the listed elements (e.g., preventing and/ortreating an affliction means preventing, treating, or both treating andpreventing further afflictions).

Also herein, all numbers are assumed to be modified by the term “about”and preferably by the term “exactly.” As used herein in connection witha measured quantity, the term “about” refers to that variation in themeasured quantity as would be expected by the skilled artisan making themeasurement and exercising a level of care commensurate with theobjective of the measurement and the precision of the measuringequipment used. Herein, “up to” a number (e.g., up to 50) includes thenumber (e.g., 50). Also herein, the recitations of numerical ranges byendpoints include all numbers subsumed within that range as well as theendpoints (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.)and any sub-ranges (e.g., 1 to 5 includes 1 to 4, 1 to 3, 2 to 4, etc.).

The complete disclosures of the patents, patent documents, andpublications cited herein are incorporated by reference in theirentirety as if each were individually incorporated. To the extent thatthere is any conflict or discrepancy between the present disclosure andthe disclosure in any document that is incorporated by reference, thisdisclosure as written will control.

What is claimed is:
 1. A pharmaceutical composition in the form of anorally disintegrating tablet and comprising an amorphous soliddispersion, the amorphous solid dispersion comprising nilotinib freebase and a polymer; wherein the nilotinib and the polymer are present inthe amorphous solid dispersion in a w/w ratio of 35:65 to 80:20(nilotinib:polymer); wherein the polymer is a hydroxypropylmethylcellulose acetate succinate; wherein the orally disintegratingtablet comprises the amorphous solid dispersion in an amount of 20% to40% by weight of the tablet; wherein the orally disintegrating tablet ischaracterized by a disintegration time of 40 seconds or less, asdetermined according to USP <701> Disintegration, using a basket-rackapparatus with disks in a medium of distilled water; and wherein theorally disintegrating tablet is characterized by a dissolution of atleast 10% release of the nilotinib into a dissolution medium within 30minutes, wherein the dissolution medium consists of 20 mM citrate bufferat pH 3.1, and the dissolution is determined according to USP <711>Dissolution using Apparatus 2 at 100 rpm.
 2. The pharmaceuticalcomposition of claim 1, wherein the amorphous solid dispersion consistsessentially of nilotinib free base and the hydroxypropyl methylcelluloseacetate succinate.
 3. The pharmaceutical composition of claim 1, whereinthe amorphous solid dispersion consists essentially of nilotinib freebase, the hydroxypropyl methylcellulose acetate succinate, and anantioxidant.
 4. The pharmaceutical composition of claim 1, wherein thenilotinib and the hydroxypropyl methylcellulose acetate succinate arepresent in the amorphous solid dispersion in a w/w ratio of 40:60 to70:30 (nilotinib:polymer).
 5. The pharmaceutical composition of claim 1,wherein the disintegration time is 30 seconds or less.
 6. Thepharmaceutical composition of claim 1, wherein the orally disintegratingtablet is palatable when free of flavorants.
 7. The pharmaceuticalcomposition of claim 1, wherein the orally disintegrating tabletcomprises 10 to 100 mg nilotinib.
 8. The pharmaceutical composition ofclaim 1, wherein the orally disintegrating tablet comprises: a) 20% to40% of the amorphous solid dispersion, by weight of the tablet; b) 20%to 75% of one or more fillers, by weight of the tablet; and c) 5% to 15%of one or more disintegrants, by weight of the tablet.
 9. Thepharmaceutical composition of claim 8, wherein the one or more fillerscomprises at least one of mannitol and microcrystalline cellulose. 10.The pharmaceutical composition of claim 8, wherein the one or morefillers comprises a combination of mannitol and microcrystallinecellulose.
 11. The pharmaceutical composition of claim 8, wherein theone or more disintegrants comprises at least one of crospovidone andcroscarmellose sodium.
 12. The pharmaceutical composition of claim 8,wherein the one or more disintegrants comprises a combination ofcrospovidone and croscarmellose sodium.
 13. The pharmaceuticalcomposition of claim 1, wherein the orally disintegrating tabletcomprises granules, the granules comprising: a) 20% to 80% of theamorphous solid dispersion, by weight of the granule; b) 15% to 60% ofone or more granulation fillers, by weight of the granule; and c) 2% to20% of one or more granulation disintegrants, by weight of the granule.14. The pharmaceutical composition of claim 13, wherein the one or moregranulation fillers comprises mannitol.
 15. The pharmaceuticalcomposition of claim 13, wherein the one or more granulationdisintegrants comprises croscarmellose sodium.
 16. The pharmaceuticalcomposition of claim 1, wherein the orally disintegrating tabletcomprises granules, the granules comprising: a) 20% to 60% of theamorphous solid dispersion, by weight of the granule; b) 40% to 80% ofone or more granulation fillers, by weight of the granule; and c) 2% to10% of one or more granulation disintegrants, by weight of the granule.17. The pharmaceutical composition of claim 16, wherein the one or moregranulation fillers comprises co-processed mannitol starch.
 18. Thepharmaceutical composition of claim 16, wherein the one or moregranulation fillers comprises microcrystalline cellulose.
 19. Thepharmaceutical composition of claim 16, wherein the one or moregranulation fillers comprises a combination of co-processed mannitolstarch and microcrystalline cellulose.
 20. The pharmaceuticalcomposition of claim 16, wherein the one or more granulationdisintegrants comprises crospovidone.
 21. The pharmaceutical compositionof claim 1, wherein the orally disintegrating tablet comprises granulesand extra-granular excipients.
 22. The pharmaceutical composition ofclaim 21, wherein the extra-granular excipients comprise one or moretablet disintegrants.
 23. The pharmaceutical composition of claim 21,wherein the orally disintegrating tablet comprises: a) 20% to 80% of thegranules, by weight of the tablet; and b) 20% to 80% of theextra-granular excipients, by weight of the tablet.
 24. Thepharmaceutical composition of claim 23, wherein the extra-granularexcipients comprise one or more tablet fillers and one or more tabletdisintegrants.
 25. The pharmaceutical composition of claim 24, whereinthe one or more tablet fillers comprises mannitol.
 26. Thepharmaceutical composition of claim 24, wherein the one or more tabletfillers comprises a combination of mannitol and microcrystallinecellulose.
 27. The pharmaceutical composition of claim 24, wherein theone or more tablet disintegrants comprises a combination of crospovidoneand croscarmellose sodium.
 28. The pharmaceutical composition of claim21, wherein the orally disintegrating tablet comprises: a) 80% to 99.5%of the granules, by weight of the tablet; and b) 0.5% to 20% of theextra-granular excipients, by weight of the tablet.
 29. Thepharmaceutical composition of claim 28, wherein the extra-granularexcipients comprise one or more tablet disintegrants, wherein the one ormore tablet disintegrants comprises crospovidone.
 30. The pharmaceuticalcomposition of claim 29, wherein the granules comprise one or moregranulation disintegrants, wherein the one or more granulationdisintegrants comprises crospovidone.